chr12-114385521-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_181486.4(TBX5):c.710G>A(p.Arg237Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_181486.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBX5 | NM_181486.4 | c.710G>A | p.Arg237Gln | missense_variant | Exon 7 of 9 | ENST00000405440.7 | NP_852259.1 | |
TBX5 | NM_000192.3 | c.710G>A | p.Arg237Gln | missense_variant | Exon 7 of 9 | NP_000183.2 | ||
TBX5 | NM_080717.4 | c.560G>A | p.Arg187Gln | missense_variant | Exon 6 of 8 | NP_542448.1 | ||
TBX5 | XM_017019912.2 | c.758G>A | p.Arg253Gln | missense_variant | Exon 7 of 9 | XP_016875401.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TBX5 | ENST00000405440.7 | c.710G>A | p.Arg237Gln | missense_variant | Exon 7 of 9 | 1 | NM_181486.4 | ENSP00000384152.3 | ||
TBX5 | ENST00000310346.8 | c.710G>A | p.Arg237Gln | missense_variant | Exon 7 of 9 | 1 | ENSP00000309913.4 | |||
TBX5 | ENST00000349716.9 | c.560G>A | p.Arg187Gln | missense_variant | Exon 6 of 8 | 1 | ENSP00000337723.5 | |||
TBX5 | ENST00000526441.1 | c.710G>A | p.Arg237Gln | missense_variant | Exon 6 of 7 | 1 | ENSP00000433292.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
Holt-Oram syndrome Pathogenic:5
The Arg237Gln variant in TBX5 has been reported in two individuals with Holt-Ora m syndrome and segregated with disease in one affected relative (Basson 1997, Ba sson 1999). This variant has not been identified in large population studies, bu t is listed in dbSNP without frequency information (rs104894378). The TBX5 gene encodes a transcription factor and the variant is located in the DNA binding dom ain and functional studies indicate that it affects protein function (Ghosh 2001 , Hiroi 2001, Fan 2003, Fan 2009, Stirnimann 2010, Wang 2011). Computational ana lyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, an d SIFT) also support that this variant may impact the protein as does the presen ce of other variants at this position that have been detected in individuals wit h Holt Oram syndrome (Arg237Pro, Arg237Trp; Basson 1999, Boogerd 2010). In summa ry, the Arg237Gln variant is likely pathogenic, though additional studies are re quired to fully establish its clinical significance. -
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PS3, PM1, PM5, PP3, PS4_supporting -
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not provided Pathogenic:1
In vitro functional studies demonstrated a damaging effect through reduced DNA-binding activity, reduced transcriptional activation, and failure to act with NKX2.5 in transcriptional activation in comparison to wild-type (Fan et al., 2003; Zhou et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28337273, 20519243, 12499378, 19648116, 28164238, 30552424, 20450920, 11431700, 21897873, 12789647, 10077612, 32449309, 8988165, 25986147, 25680289, 11555635) -
Aortic valve disease 2 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 237 of the TBX5 protein (p.Arg237Gln). This variant is present in population databases (rs104894378, gnomAD 0.01%). This missense change has been observed in individual(s) with Holt-Oram syndrome (PMID: 8988165, 12789647). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7993). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TBX5 protein function. Experimental studies have shown that this missense change affects TBX5 function (PMID: 11555635, 12499378). This variant disrupts the p.Arg237 amino acid residue in TBX5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10077612, 12499378, 12789647, 20519243). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.R237Q variant (also known as c.710G>A), located in coding exon 6 of the TBX5 gene, results from a G to A substitution at nucleotide position 710. The arginine at codon 237 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in multiple individuals with clinical diagnoses of Holt-Oram syndrome (Basson CT et al. Nat. Genet., 1997 Jan;15:30-5; Debeer P et al. Clin. Orthop. Relat. Res., 2007 Sep;462:20-6; Vanlerberghe C et al. Eur. J. Hum. Genet., 2019 03;27:360-368). Functional studies suggest that this alteration may affect TBX5 binding affinity to other transcription factors (Ghosh TK et al. Hum. Mol. Genet., 2001 Sep;10:1983-94; Fan C et al. J. Biol. Chem., 2003 Mar;278:8780-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at