Submissions for variant NM_181486.4(TBX5):c.710G>A (p.Arg237Gln)

gnomAD frequency: 0.00001  dbSNP: rs104894378

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000008457	SCV000205351	likely pathogenic	Holt-Oram syndrome	2013-04-12	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000196777	SCV000250816	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000474989	SCV000552109	pathogenic	Aortic valve disease 2	2023-11-24	criteria provided, single submitter	clinical testing	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). Advanced 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 at Invitae 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.
Ambry Genetics	RCV002362569	SCV002663140	likely pathogenic	Cardiovascular phenotype	2023-04-21	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000008457	SCV002809870	pathogenic	Holt-Oram syndrome	2021-12-13	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000008457	SCV003932238	pathogenic	Holt-Oram syndrome	2023-01-19	criteria provided, single submitter	clinical testing	PS3, PM1, PM5, PP3, PS4_supporting
OMIM	RCV000008457	SCV000028665	pathogenic	Holt-Oram syndrome	1999-03-16	no assertion criteria provided	literature only
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000008457	SCV000920860	pathogenic	Holt-Oram syndrome	2018-06-14	no assertion criteria provided	clinical testing