| Mutation (DNA)
|
Mutation (peptide)
|
CHD
|
Reference
|
Other features
|
Inheritence
|
Additional info.
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 c.381-408del27bp
|
|
ASD
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PMID:12624158
|
Familial HOS: CHD (ASD, VSD, MVP) and limb defects (not further specified (9/25 affected members))
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Dominant Familial
|
 show  hide
| Genetic evidence
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Segregating in family in 25/25 affected members (no CHD 6/25; ASD/VSD 11/25; bradycardie or MVP 9/25); 0/200 normal controls
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| in silico prediction
|
In-frame deletion. Protein-producing mutation. Aberrant protein shows drastically reduced nuclear localization and diminished DNA-binding ability
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| Functional studies
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| Comments
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| c.381-408del27bp
|
|
VSD
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PMID:12624158
|
Familial HOS: CHD (ASD, VSD, MVP) and limb defects (not further specified (9/25 affected members))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 25/25 affected members (no CHD 6/25; ASD/VSD 11/25; bradycardie or MVP 9/25); 0/200 normal controls
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| in silico prediction
|
In-frame deletion. Protein-producing mutation. Aberrant protein shows drastically reduced nuclear localization and diminished DNA-binding ability
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| Functional studies
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| Comments
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| NM_000192.3:c.1024delT
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Q99593.2:p.Y342fsX393
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VSD
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PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral limb defects (aplastic thumb (B), radial deviation (B), hypoplastic humerus, dypsplastic or aplastic radius)
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Dominant Familial
|
show hide
| Genetic evidence
|
No details about segregation of CHD in the family
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| in silico prediction
|
Frameshift mutation; truncated at codon 393; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking residues at the C-terminal region
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| Functional studies
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| Comments
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| c.510+1G>T
|
Splice site mutation
|
ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
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| Comments
|
Subject carries two de novo alterations.
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| c.756-3C>G
|
Splice site mutation
|
ASD
|
PMID:15710732
|
Sporadic HOS with CHD (ASD, VSD) and bilateral thumb anomalies
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
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| in silico prediction
|
Splice site mutation; partial consent at the 3' acceptor splice site of intron 7â€â€ÂÂÂfor example in Mus musculus; 0/50 normal controls
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| Functional studies
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| Comments
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| c.755+2 T > G
|
Splice site mutation
|
VSD
|
PMID:16183809
|
Sporadic HOS: VSD and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.362+1G>T
|
Splice site mutation
|
VSD
|
PMID:16183809
|
Familial HOS with VSD and preaxial radial ray defect (not further specified)
|
Dominant Familial
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
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| Comments
|
No details on segregation of CHDs in the family provided.
|
|
| c.510+1G>T
|
Splice site mutation
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
Subject carries two de novo alterations.
|
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| c.756-1G>A
|
Splice site mutation
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (VSD, conduction defect) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.756-3C>G
|
Splice site mutation
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD) and bilateral thumb anomalies
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
|
| in silico prediction
|
Splice site mutation; partial consent at the 3' acceptor splice site of intron 7â€â€ÂÂÂfor example in Mus musculus; 0/50 normal controls
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| Functional studies
|
|
| Comments
|
|
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| c.510+1G>T
|
Splice site mutation
|
Aortic coarctation
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Splicing mutations resulting in a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
Subject carries two de novo alterations.
|
|
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|
p.315Q>ter
|
ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD) and preaxial radial ray defects (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
|
| Functional studies
|
|
| Comments
|
Wrong mutation residue (nucleotide) in table 2.
|
|
|
|
p.315Q>ter
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD) and preaxial radial ray defects (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
|
| Functional studies
|
|
| Comments
|
Wrong mutation residue (nucleotide) in table 2.
|
|
| c.426-427insC
|
p.A143fsX182
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (VSD, ASD) and uni- or bilateral limb defects (absent or hypoplastic thumb, radio-ulnar synostosis, absent ulna, hypoplastic or absent radius (L), hypoplastic humerus (L), extra digit (R1), triphalangeal thumb (L))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 4/4 affected members (4/4 VSD; 2/4 muscular VSD; ASD 1/4; ASD2 1/4)
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated within the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
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| c.426-427insC
|
p.A143fsX182
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (VSD, ASD) and uni- or bilateral limb defects (absent or hypoplastic thumb, radio-ulnar synostosis, absent ulna, hypoplastic or absent radius (L), hypoplastic humerus (L), extra digit (R1), triphalangeal thumb (L))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 4/4 affected members (4/4 VSD; 2/4 muscular VSD; ASD 1/4; ASD2 1/4)
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated within the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.100-101insG
|
p.A34fsX60
|
ASD
|
PMID:12789647
|
Ulnar deviation of distal phalanx (B); abnormal shoulder girdle
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated prior to the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.100delG
|
p.A34fsX65
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects(hypoplastic or absent thumb(s), hypoplastic digit (B2-5), hypoplastic radius, hypoplastic ulna, hypoplastic humerus, hypoplastic chest wall, abnormal shoulder girdle, hypoplastic scapula; radial deviation of arm
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members, with variable penetrance ((1/3 no CHD; 1/3 ASD2 + muscVSD; 1/3 swiss cheese VSD + AV canal); 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated prior to the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.100dupG
|
p.A34fsX65
|
ASD
|
PMID:16917909
|
Familial HOS with CHD (AV dissociation, ASD, MVI) and uni- or bilateral limb defects (hypoplastic left thumbs, prolonged first metacarpal) and anophtalmia.
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (AV dissociation 1/3; ASD 2/3; MVI 1/3)
|
| in silico prediction
|
Frameshift mutation; truncated at codon 65; frameshift in TBX5 predicted to encode a product that, if translated, would prematurely truncated prior to the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.100delG
|
p.A34fsX65
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects(hypoplastic or absent thumb(s), hypoplastic digit (B2-5), hypoplastic radius, hypoplastic ulna, hypoplastic humerus, hypoplastic chest wall, abnormal shoulder girdle, hypoplastic scapula; radial deviation of arm).
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members, with variable penetrance ((1/3 no CHD; 1/3 ASD2 + muscVSD; 1/3 swiss cheese VSD + AV canal); 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated prior to the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.710G>A
|
p.Arg237Gln (R237Q)
|
Patent foramen ovale (PFO)
|
PMID:12789647
|
Familial HOS: CHD (ASD, PFO) and uni- or bilateral (B) limb defects (hypoplastic thenar eminence (L), hypoplastic chest wall; triphalangeal thumb (B), absent digit (L1, L2, R1), hypoplastic humerus, radius, ulna (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (1/3 PFO; 2/3 ASD2); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). Arg237 corresponding to Arg284 in TBX3, are predicted to disrupt the position and stability of the C-terminal a helix, thereby affecting binding of TBX5 to the minor groove of the DNA target (Basson et al. 1999).
|
| Functional studies
|
|
| Comments
|
|
|
| c.709C>T
|
p.Arg237Gln (R237Q)
|
ASD
|
PMID:8988165
|
Familial HOS: CHD (ASD, AV conduction defect) and uni- or bilateral limb defects (triphalangeal thumb, carpal bone deformity, phocomelia, ectromelia, digitilazed thenar bones, hypoplastic radius, aplastic radius, aplastic thumb)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family 18/18 affected members (6/18 ASD; 1/18 AV conduction defect; 2/18 no cardiac evaluation); 0/100 normal controls
|
| in silico prediction
|
Protein-producing mutation in highly conserved residue at the carboxyl end of the T-box residue. Aberrant proteins show drastically reduced nuclear localisation and diminished DNA-binding ability. There is also a loss of physical interaction between mutant TBX5 and NKX2.5.
|
| Functional studies
|
|
| Comments
|
|
|
| c.710G>A
|
p.Arg237Gln (R237Q)
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD, PFO) and uni- or bilateral (B) limb defects (hypoplastic thenar eminence (L), hypoplastic chest wall; triphalangeal thumb (B), absent digit (L1, L2, R1), hypoplastic humerus, radius, ulna (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (1/3 PFO; 2/3 ASD2); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). Arg237 corresponding to Arg284 in TBX3, are predicted to disrupt the position and stability of the C-terminal a helix, thereby affecting binding of TBX5 to the minor groove of the DNA target (Basson et al. 1999).
|
| Functional studies
|
|
| Comments
|
|
|
| c.709C>T
|
p.Arg237Trp (R237W)
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD) and uni- or bilateral (B) limb defects (hypoplastic thumb (L), limited supination of forearm (L))
|
Dominant Familial
|
show hide
| Genetic evidence
|
in family in 2/2 affected members (1/2 no CHD; 1/2 ASD2)
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). Arg237 corresponding to Arg284 in TBX3, are predicted to disrupt the position and stability of the C-terminal a helix, thereby affecting binding of TBX5 to the minor groove of the DNA target (Basson et al. 1999).
|
| Functional studies
|
|
| Comments
|
|
|
| c.709C>T
|
p.Arg237Trp (R237W)
|
VSD
|
PMID:12789647
|
Sporadic HOS with CHD (AV canal, VSD (membranous)) and limb defects (hypoplastic digit (L1), absent digit (R1), Hypoplastic radius (B)).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). Arg237 corresponding to Arg284 in TBX3, are predicted to disrupt the position and stability of the C-terminal a helix, thereby affecting binding of TBX5 to the minor groove of the DNA target (Basson et al. 1999).
|
| Functional studies
|
|
| Comments
|
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
ASD
|
PMID:12789647
|
Hypoplastic triphalangeal thumb (B), hypoplastic radius (L)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
A partial TBX5 protein that includes the T box could be produced in the presence of p.279Arg>ter. However, the protein would still lack much of the C-terminal domain of TBX5. The mechanism(s) by which p.279Arg>ter disrupt the function of TBX5 is unclear, because deletion of the entire C-terminal region (amino acids 238–518 inclusive) enhances DNA binding affinity, whereas deletion of amino acids 242 onwards results in loss of binding to the T binding element (Ghosh et al. 2001).
|
| Functional studies
|
|
| Comments
|
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
ASD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
ASD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD, multiple VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
ASD
|
PMID:8988164
|
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
ASD
|
PMID:11183182
|
Sporadic HOS with ASD and limb defects (bilateral absent thumbs, right radial aplasia, left radial hypoplasia).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains
|
| Functional studies
|
|
| Comments
|
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
Common atrium (virtual absence of atrial septum)
|
PMID:15710732
|
Sporadic HOS with CHD (common atrium and complete atrioventricular canal) and limb defects (left phocomelia, hypoplastic radius, right hypoplastic thumb)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
|
| in silico prediction
|
A partial TBX5 protein that includes the T box could be produced in the presence of p.279Arg>ter. However, the protein would still lack much of the C-terminal domain of TBX5. The mechanism(s) by which p.279Arg>ter disrupt the function of TBX5 is unclear, because deletion of the entire C-terminal region (amino acids 238–518 inclusive) enhances DNA binding affinity, whereas deletion of amino acids 242 onwards results in loss of binding to the T binding element (Ghosh et al. 2001).
|
| Functional studies
|
|
| Comments
|
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
VSD
|
PMID:12789647
|
Hypoplastic triphalangeal thumb (B), hypoplastic radius (L)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 nomral controls
|
| in silico prediction
|
A partial TBX5 protein that includes the T box could be produced in the presence of p.279Arg>ter. However, the protein would still lack much of the C-terminal domain of TBX5. The mechanism(s) by which p.279Arg>ter disrupt the function of TBX5 is unclear, because deletion of the entire C-terminal region (amino acids 238–518 inclusive) enhances DNA binding affinity, whereas deletion of amino acids 242 onwards results in loss of binding to the T binding element (Ghosh et al. 2001).
|
| Functional studies
|
|
| Comments
|
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
VSD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating 0/100 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
VSD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD, multiple muscular VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.835C>T
|
p.Arg279ter (R279X)
|
VSD
|
PMID:8988164
|
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Dominant Sporadic
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show hide
| Genetic evidence
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0/100 normal controls
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| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
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| Functional studies
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| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
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|
| c.504delT
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p.F168fsX173
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ASD
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PMID:16917909
|
Familial HOS with CHD (ASD2, VSD, PDA, MVP + TVP + regurgitation) and uni- or bilateral limb defects (triphalangeal thumb with ulnar deviation of distal phalanx, aplastic or hypoplastic thumb, shortened forearms, limited pro- and supination of forearms, abnormal shoulder girdle with limited range of motion)
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Dominant Familial
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show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD II 1/2, VSD 1/2, PDA 1/2; MVP+TVP+regurgitation 1/2)
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| in silico prediction
|
Frameshift mutation; truncated at codon 173; truncated TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
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| Comments
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| c.280delC
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p.F168fsX173
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VSD
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PMID:16917909
|
Familial HOS with CHD (VSD, ASD2, multiple VSD) and uni- or bilateral limb defects (aplastic thumb, triphalangeal thumb, hypoplastic claviculae and radii, hypoplastic left ulna)
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Dominant Familial
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show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (VSD 3/3, ASD 1/3)
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| in silico prediction
|
Frameshift mutation, premature stop at codon 123; causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
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| Comments
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| c.451C>T
|
p.Gln151ter (Q151X)
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ASD
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PMID:16917909
|
Familial HOS with CHD (ASD2, MVI, AV block I) and uni- or bilateral limb defects (triphalangeal digitalized thumb with ulnar deviation of distal phalanx)
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Dominant Familial
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show hide
| Genetic evidence
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No details about segregation of CHD in the family
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| in silico prediction
|
Nonsense mutation; truncated at codon 151; truncated TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.751C>T
|
p.Gln251ter (Q251X)
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ASD
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PMID:16183809
|
Sporadic HOS with ASD and preaxial radial ray defect (not further specified).
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Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
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| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
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| Functional studies
|
|
| Comments
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|
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| c.1084C>T
|
p.Gln362ter (Q362X)
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ASD
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PMID:15710732
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Sporadic HOS with CHD (ASD, VSD, pulmonary vein anomaly) and limb defects (bilateral triphalangeal thumb, movement restriction of shoulder joints)
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Dominant Sporadic
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show hide
| Genetic evidence
|
de novo 0/50 normal controls
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| in silico prediction
|
Nonsense mutation; truncated at codon 362; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal.
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| Functional studies
|
|
| Comments
|
|
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| c.1084C>T
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p.Gln362ter (Q362X)
|
VSD
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PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, pulmonary vein anomaly) and limb defects (bilateral triphalangeal thumb, movement restriction of shoulder joints)
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Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
|
| in silico prediction
|
Nonsense mutation; truncated at codon 362; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal.
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| Functional studies
|
|
| Comments
|
|
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| c.145C>A
|
p.Gln49Lys (Q49K)
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ASD
|
PMID:10842287
|
Familial HOS: CHD (ASD) and uni- or bilateral (B) limb defects (small thumbs, absent left middle finger, syndactyly between right middle and ring fingers, small left thumb)
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Dominant Familial
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show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD2/2); 0/50 normal controls
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| in silico prediction
|
Protein-producing mutation. Aberrant proteins show drastically reduced nuclear localisation, but bind DNA normally. These mutations may lead to loss of physical interaction between TBX5 and NKX2.5 but do not disrupt TBX5 interactions with GATA4.
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| Functional studies
|
|
| Comments
|
|
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| c.205G>T
|
p.Glu69ter (E69X)
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ASD
|
PMID:8988165
|
Familial HOS: no clinical data available
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Dominant Familial
|
show hide
| Genetic evidence
|
no clinical data available; 0/100 normal controls
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| in silico prediction
|
Nonsense mutation causing a truncated at codon 69, resulting in a TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.584G>C
|
p.Gly195Ala (G195A)
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Patent foramen ovale (PFO)
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PMID:12789647
|
Sporadic HOS with CHD (PFO, asymmetrical aortic valve), limb defects (hypoplastic digit 1 (B), absent scaphoid), abdominal situs inversus and vertebral defects (C2C3 and C6C7 fusion)
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Dominant Sporadic
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show hide
| Genetic evidence
|
de novo 0/150 normal controls
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| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). Gly195 is analogous to Lys242 in TBX3. Lys242 is located within a short a helix that is not present in the Xbra crystal structure of the DNA-binding domain of TBX3 (Muller and Herrmann 1997). This helix is on the surface of the core region distal to the DNA-binding residues and is positioned next to a stretch of four amino acid residues predicted to make weak interactions with a second TBX3 monomer in complex with the palindromic binding site. Since the function of this part of the protein has not been established, the impact of the Gly195Ala substitution in TBX5 cannot be predicted.
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| Functional studies
|
|
| Comments
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|
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| c.238G>A
|
p.Gly80Arg (G80R)
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ASD
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PMID:10077612
|
Familial HOS: CHD (ASD, VSD, Conduction defect, left VCS, PDA) and uni- or bilateral limb defects (triphalangeal thumb 3/19; carpal bone deformity 17/19; hypoplastic or deformed radius 9/19; digitalized thenar bones 9/19; unilateral aplastic thumb 1/19; unilateral aplastic digit 1/19; no data available 1/19)
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Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in 19/19 affected members (ASD 7/19; VSD 11/19; Conduction defect 13/19; left VCS 1/19; PDA 2/19)
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| in silico prediction
|
Missense mutation in the T-box; predicting the consequences of this mutation by mapping onto the three-dimensional structure of the Xbra T-box: the Gly80Arg mutation occurs near the amino-terminal end of the T-box, designated the ab-loop. Replacement of glycine residue 80 by arginine should therefore alter the ab-loop structure and potentially impair interactions with the major groove of target DNA.
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| Functional studies
|
|
| Comments
|
|
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| c.238G>A
|
p.Gly80Arg (G80R)
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VSD
|
PMID:10077612
|
Familial HOS: CHD (ASD, VSD, Conduction defect, left VCS, PDA) and uni- or bilateral limb defects (triphalangeal thumb 3/19; carpal bone deformity 17/19; hypoplastic or deformed radius 9/19; digitalized thenar bones 9/19; unilateral aplastic thumb 1/19; unilateral aplastic digit 1/19; no data available 1/19)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in 19/19 affected members (ASD 7/19; VSD 11/19; Conduction defect 13/19; left VCS 1/19; PDA 2/19)
|
| in silico prediction
|
Missense mutation in the T-box; predicting the consequences of this mutation by mapping onto the three-dimensional structure of the Xbra T-box: the Gly80Arg mutation occurs near the amino-terminal end of the T-box, designated the ab-loop. Replacement of glycine residue 80 by arginine should therefore alter the ab-loop structure and potentially impair interactions with the major groove of target DNA.
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| Functional studies
|
|
| Comments
|
|
|
| c.813_814delCA
|
p.H271fsX293
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ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, conduction, Long QT syndrome)and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
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| Functional studies
|
|
| Comments
|
|
|
| c.813_814delCA
|
p.H271fsX293
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, conduction, Long QT syndrome)and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
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| Functional studies
|
|
| Comments
|
|
|
| c.509A>T
|
p.His170Leu (H170L)
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ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Missense mutation in the T-box.
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| Functional studies
|
|
| Comments
|
Subject carries two de novo alterations.
|
|
| c.509A>T
|
p.His170Leu (H170L)
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VSD
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PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Missense mutation in the T-box.
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| Functional studies
|
|
| Comments
|
Subject carries two de novo alterations.
|
|
| c.509A>T
|
p.His170Leu (H170L)
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Aortic coarctation
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD, CoAo) and preaxial radial ray defect (not further specified).
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Missense mutation in the T-box.
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| Functional studies
|
|
| Comments
|
Subject carries two de novo alterations.
|
|
| c.161T>C
|
p.Ile54Thr (I54T)
|
ASD
|
PMID:10842287
|
Absent left thumb
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
|
| in silico prediction
|
Protein-producing mutation. Aberrant proteins show drastically reduced nuclear localisation, but bind DNA normally. These mutations may lead to loss of physical interaction between TBX5 and NKX2.5 but do not disrupt TBX5 interactions with GATA4.
|
| Functional studies
|
|
| Comments
|
|
|
| c.798delA
|
p.K266fsX393
|
ASD
|
PMID:12789647
|
Absent thumb (B), hypoplastic radius (B)
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Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
A partial TBX5 protein that includes the T box could be produced in the presence of 798delA. However, the protein would still lack much of the C-terminal domain of TBX5. The mechanism(s) by which 798delA disrupt the function of TBX5 is unclear, because deletion of the entire C-terminal region (amino acids 238–518 inclusive) enhances DNA binding affinity, whereas deletion of amino acids 242 onwards results in loss of binding to the T binding element (Ghosh et al. 2001).
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| Functional studies
|
|
| Comments
|
|
|
| c.798delA
|
p.K266fsX393
|
VSD
|
PMID:12789647
|
Absent thumb (B), hypoplastic radius (B)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
A partial TBX5 protein that includes the T box could be produced in the presence of 798delA. However, the protein would still lack much of the C-terminal domain of TBX5. The mechanism(s) by which 798delA disrupt the function of TBX5 is unclear, because deletion of the entire C-terminal region (amino acids 238–518 inclusive) enhances DNA binding affinity, whereas deletion of amino acids 242 onwards results in loss of binding to the T binding element (Ghosh et al. 2001).
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| Functional studies
|
|
| Comments
|
|
|
| c.456delC
|
p.L152fsX173
|
ASD
|
PMID:12789647
|
Absent digit (B1), absent radius (B)
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Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated within the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.939delG
|
p.L313fsX393
|
ASD
|
PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral limb defects (digitalized thumb (B), limited pro- and supination of forearms, hypoplastic chest wall, brachydactyly II-V (B), ulnar deviation of distal phalanx of the thumb)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD 2/2; VSD 1/2)
|
| in silico prediction
|
Frameshift mutation; truncated at codon 393; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking residues at the C-terminal region
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| Functional studies
|
|
| Comments
|
|
|
| c.939delG
|
p.L313fsX393
|
VSD
|
PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral limb defects (digitalized thumb (B), limited pro- and supination of forearms, hypoplastic chest wall, brachydactyly II-V (B), ulnar deviation of distal phalanx of the thumb)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD 2/2; VSD 1/2)
|
| in silico prediction
|
Frameshift mutation; truncated at codon 393; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking residues at the C-terminal region
|
| Functional studies
|
|
| Comments
|
|
|
| c.280delC
|
p.L94fsX123
|
ASD
|
PMID:15710732
|
Familial HOS with CHD (VSD, ASD2, multiple VSD) and uni- or bilateral limb defects (aplastic thumb, triphalangeal thumb, hypoplastic claviculae and radii, hypoplastic left ulna)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (VSD 3/3, ASD 1/3)
|
| in silico prediction
|
Frameshift mutation, premature stop at codon 123; causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.280delC
|
p.L94fsX123
|
VSD
|
PMID:16183809
|
Familial HOS with CHD (VSD, ASD2, multiple VSD) and uni- or bilateral limb defects (aplastic thumb, triphalangeal thumb, hypoplastic claviculae and radii, hypoplastic left ulna)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (VSD 3/3, ASD 1/3)
|
| in silico prediction
|
Frameshift mutation, premature stop at codon 123; causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.593_594insA
|
p.N198fsX208
|
ASD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD, multiple VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.593_594insA
|
p.N198fsX208
|
VSD
|
PMID:8988164
|
Familial HOS: CHD (ASD, VSD, multiple VSD) and uni- or bilateral limb defects (bilateral triphalangeal thumbs, absent thumbs, radial aplasia)
|
Dominant Familial
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
Clinical details of CHD type and segregation of CHDs in this family were not provided.
|
|
| c.416delC
|
p.P139fsX149
|
ASD
|
PMID:10842287
|
Familial HOS: CHD (ASD) and uni- or bilateral (B) limb defects (absent left arm and thumb, absent right forearm and thumb, curved radii and ulnae, absent thumbs (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD 2/2); 0/50 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.467_468insA
|
p.Q156fsX182
|
ASD
|
PMID:15710732
|
Sporadic HOS with ASD2 and bilateral thumb anomalies
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/50 normal controls
|
| in silico prediction
|
Frameshift mutation, premature stop at codon 182; truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.400-401insC
|
p.R134fsX182
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (VSD, ASD) and uni- or bilateral (B) limb defects (absent or digitalized thumb (B), hypoplastic radius (R))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 5/5 affected members (4/5 VSD; 2/5 ASD); 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated within the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.400-401insC
|
p.R134fsX182
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (VSD, ASD) and uni- or bilateral (B) limb defects (absent or digitalized thumb (B), hypoplastic radius (R))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 5/5 affected members (4/5 VSD; 2/5 ASD); 0/150 normal controls
|
| in silico prediction
|
Frameshift mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated within the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.1159_1160insA
|
p.S387fsX486
|
ASD
|
PMID:8988164
|
Sporadic HOS: no clinical details available
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/100 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
|
| Functional studies
|
|
| Comments
|
|
|
| c.1159_1160insA
|
p.S387fsX486
|
VSD
|
PMID:8988164
|
Sporadic HOS: no clinical details available
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region including the putative activator and repressor domains.
|
| Functional studies
|
|
| Comments
|
|
|
| c.587C>A
|
p.Ser196ter (S196X)
|
Tetralogy of Fallot
|
PMID:16183809
|
Sporadic HOS with CHD (VSD, ToF) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.587C>A
|
p.Ser196ter (S196X)
|
ASD
|
PMID:8988164
|
Sporadic HOS: not further specified
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
0/100 normal controls
|
| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.587C>A
|
p.Ser196ter (S196X)
|
VSD
|
PMID:12789647
|
Sporadic HOS with VSD and limb defect (triphalangeal thumb (R), absent radius (L), hypoplastic ulna (L))
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Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Nonsense mutation in TBX5 predicted to encode a product that, if translated, would prematurely truncated prior to the T box. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.587C>A
|
p.Ser196ter (S196X)
|
VSD
|
PMID:8988164
|
Sporadic HOS: not further specified
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Dominant Sporadic
|
show hide
| Genetic evidence
|
Segregating 0/100 normal controls
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| in silico prediction
|
Frameshift mutation causing a truncated TBX5 protein lacking most T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.587C>A
|
p.Ser196ter (S196X)
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (VSD, ToF) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation causing a truncated TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
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| Functional studies
|
|
| Comments
|
|
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| c.781A>T
|
p.Ser261Cys (S261C)
|
Double outlet RV
|
PMID:12789647
|
Familial HOS with CHD (DORV, AV canal), uni- or bilateral limb defects (hypoplastic distal phalanges, absent digit (L2), hypoplastic radius (L)), cleft palate, facial asymmetry, micrognathia and hypoplastic nails.
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (2/3 no CHD; 1/3 DORV; 1/3 AV canal); 0/150 normal controls
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| in silico prediction
|
One predicted amino acid substitution in the C-terminal domain of TBX5, farther downstream of the T box than any missense mutation reported previously. A predicted function of this region of TBX5 is to interact with modifier proteins (Ghosh et al. 2001). Consequently, this substitution might, if translated into a stable protein, alter the interaction of TBX5 with a cofactor.
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| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (syndactyly (digit 1 and 2), hypoplastic radius (B), abnormal shoulder girdle musculature)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 4/4 affected members (1/4 ASD2; 1/4 VSD; 2/4 Multiple mus-VSDs); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
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| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (hypoplastic digit (R1), limited supination of forearm (B); triphalangeal thumb, hypoplastic radius (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (1/3 no CHD; 2/3 ASD; 2/3 multiple mus-VSDs); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
|
| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
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| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
ASD
|
PMID:12789647
|
Hypoplastic metacarpal (B1), hypoplastic digit (L1), triphalangeal thumb (R), Hypoplastic radius (B)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
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| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (hypoplastic digit (R1), limited supination of forearm (B); triphalangeal thumb, hypoplastic radius (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (1/3 no CHD; 2/3 ASD; 2/3 multiple mus-VSDs); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
|
| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (syndactyly (digit 1 and 2), hypoplastic radius (B), abnormal shoulder girdle musculature)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 4/4 affected members (1/4 ASD2; 1/4 VSD; 2/4 Multiple mus-VSDs); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
|
| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
VSD
|
PMID:12789647
|
Hypoplastic metacarpal (B1), hypoplastic digit (L1), triphalangeal thumb (R), Hypoplastic radius (B)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
|
| Functional studies
|
|
| Comments
|
|
|
| c.668C>T
|
p.Thr223Met (T223M)
|
VSD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD, VSD) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Thr223 corresponds to residue Thr270 in TBX3. Thr270 is in a helix 3, where the side chain contacts DNA phosphate backbone atoms, and projects into a relatively open environment in the major groove. Helix 3 and the preceding loop (residues 264–268 in TBX3) make important contacts in the major groove. Thus, substitution of residue Thr270 is expected to influence DNA recognition residues that normally contact the major groove.
|
| Functional studies
|
|
| Comments
|
|
|
| c.361T>G
|
p.Trp121Gly (W121G)
|
ASD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (hypoplastic radius (L), hypoplastic chest wall; narrow shoulders; hypoplastic thumb (L1), fused radialulnar joint (L), clinodactyly (B5))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 5/5 affected members (1/5 no CHD; 4/5 ASD; 1/5 multiple VSD); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Trp121 corresponds to TBX3 residue Trp170 in the lid structure where it packs against the core b barrel. The Trp121Gly substitution in TBX5 is predicted to destabilize the lid structure, which would likely alter the folding or stability of TBX5 and disrupt protein-DNA interactions.
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| Functional studies
|
|
| Comments
|
|
|
| c.361T>G
|
p.Trp121Gly (W121G)
|
VSD
|
PMID:12789647
|
Familial HOS: CHD (ASD, VSD) and uni- or bilateral (B) limb defects (hypoplastic radius (L), hypoplastic chest wall; narrow shoulders; hypoplastic thumb (L1), fused radialulnar joint (L), clinodactyly (B5))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 5/5 affected members (1/5 no CHD; 4/5 ASD; 1/5 multiple VSD); 0/150 normal controls
|
| in silico prediction
|
Missense mutation predicted to result in substitution of an amino acid residue of TBX5 that is highly conserved among species, located within the DNA-binding domain of TBX5. The predicted structure of TBX5 mutants was compared to wild-type TBX5 by creating a model of the DNA-binding domain of TBX5 based on the crystal structure of TBX3 (Coll et al. 2002). TBX5 residue Trp121 corresponds to TBX3 residue Trp170 in the lid structure where it packs against the core b barrel. The Trp121Gly substitution in TBX5 is predicted to destabilize the lid structure, which would likely alter the folding or stability of TBX5 and disrupt protein-DNA interactions.
|
| Functional studies
|
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
Patent foramen ovale (PFO)
|
PMID:15710732
|
Familial HOS with CHD (ASD2, PFO) and uni- or bilateral limb defects (hypoplastic thumbs, movement restriction of elbow and shoulder joints).
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (ASD 3/3, PFO 1/3)
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a TBX5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
ASD
|
PMID:12818525
|
Familial HOS: CHD (ASD) and uni- or bilateral limb defects (uni- or bilateral absent thumbs, hypoplastic deltoid muscles, triphalangeal thumb, absent or hypoplastic radius)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating 3/3 affected members (ASD 3/3); no mutations in unaffected family members; 0/100 normal controls
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a TBX5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
Truncation mutations in TBX5 located in exon 6 show similarity to mutations in the zebrafish homologue which are predicted to encode truncated proteins that cannot bind, and therefore, cannot activate target DNA
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
ASD
|
PMID:12818525
|
Familial HOS: CHD (ASD) and uni- or bilateral limb defects (hypoplastic thumbs (L>R), hypoplastic deltoid muscles)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating 3/6 affected members (ASD 3/3); no mutations in unaffected family members; 0/100 normal controls
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a tbx5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
Truncation mutations in TBX5 located in exon 6 show similarity to mutations in the zebrafish homologue which are predicted to encode truncated proteins that cannot bind, and therefore, cannot activate target DNA.
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
ASD
|
PMID:16183809
|
Sporadic HOS with CHD (ASD and AV conduction defect) and preaxial radial ray defect (not further specified)
|
Dominant Sporadic
|
show hide
| Genetic evidence
|
de novo 0/200 normal controls
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a TBX5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
ASD
|
PMID:15710732
|
Familial HOS with CHD (ASD) and uni- or bilateral limb defects (hypoplastic humeri, hypoplastic musculus deltoideus, hypoplastic radius, hypoplastic or aplastic thumb, triphalangeal thumb)
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (ASD 3/3)
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a TBX5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
|
| Comments
|
|
|
| c.408C>A
|
p.Tyr136ter (Y136X)
|
ASD
|
PMID:15710732
|
Familial HOS with CHD (ASD2, PFO) and uni- or bilateral limb defects (hypoplastic thumbs, movement restriction of elbow and shoulder joints).
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (ASD 3/3, PFO 1/3)
|
| in silico prediction
|
Nonsense mutation of exon 5 resulting in a TBX5 protein lacking most of the C-terminal region; presumably leading to a truncated protein unable to bind and activate target DNA.
|
| Functional studies
|
|
| Comments
|
|
|
| c.873C>A
|
p.Tyr291ter (Y291X)
|
ASD
|
PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral (B)limb defects (hypoplastic thumb (R), triphalangeal digitalized thumb (L), Hypoplastic radius (B), Limited pro-and supination of forearms; Brachydactyly II-V (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD 1/2; VSD 1/2)
|
| in silico prediction
|
Nonsense mutation; truncated at codon 291; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region
|
| Functional studies
|
|
| Comments
|
|
|
| c.873C>A
|
p.Tyr291ter (Y291X)
|
VSD
|
PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral (B)limb defects (hypoplastic thumb (R), triphalangeal digitalized thumb (L), Hypoplastic radius (B), Limited pro-and supination of forearms; Brachydactyly II-V (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 2/2 affected members (ASD 1/2; VSD 1/2)
|
| in silico prediction
|
Nonsense mutation; truncated at codon 291; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking most of the C-terminal region
|
| Functional studies
|
|
| Comments
|
|
|
| c.641delG
|
p.V214fsX225
|
Atrioventricular septal defect
|
PMID:16917909
|
Familial HOS with AVSD and limb defects (hypoplastic thumb (B) and radial deviation (B))
|
Dominant Familial
|
show hide
| Genetic evidence
|
Segregating in family in 3/3 affected members (AVSD 1/3, no CHD 1/3, no data 1/3)
|
| in silico prediction
|
Frameshift mutation; truncated at codon 225; truncated TBX5 protein lacking T-box residues: nonfunctional protein/nonsense-mediated mRNA degradation causing haploinsufficiency. Since deletion of even the most C-terminal amino acid residues of the T box results in loss of TBX5 binding to its consensus binding sequence in vitro (Ghosh et al. 2001), these mutations likely represent null alleles.
|
| Functional studies
|
|
| Comments
|
|
|
| c.1024delT
|
p.Y342fsX393
|
ASD
|
PMID:16917909
|
Familial HOS with CHD (VSD, ASD) and uni- or bilateral limb defects (aplastic thumb (B), radial deviation (B), hypoplastic humerus, dypsplastic or aplastic radius)
|
Dominant Familial
|
show hide
| Genetic evidence
|
No details about segregation of CHD in the family
|
| in silico prediction
|
Frameshift mutation; truncated at codon 393; causing a truncated TBX5 protein containing only the DNA-binding motif and lacking residues at the C-terminal region
|
| Functional studies
|
|
| Comments
|
|
|
ensembl: ENSG00000089225
OMIM: 601620
Search miRBase for TBX5
Expression patterns from 4DXPress: TBX5
MGI: MGI:102541
ZFIN: ZDB-GENE-991124-7
Wikipedia: TBX5
Search Wikiproteins: TBX5
Search Genetic Association Database: TBX5
Search GeneTests: TBX5
CHeartED: TBX5
