ClinVar Miner

Submissions for variant NM_181486.4(TBX5):c.781A>T (p.Ser261Cys)

gnomAD frequency: 0.00001  dbSNP: rs377625550
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622169 SCV000735448 uncertain significance Cardiovascular phenotype 2023-06-20 criteria provided, single submitter clinical testing The p.S261C variant (also known as c.781A>T), located in coding exon 7 of the TBX5 gene, results from an A to T substitution at nucleotide position 781. The serine at codon 261 is replaced by cysteine, an amino acid with dissimilar properties. This variant was previously reported in a family with features of Holt-Oram syndrome, and one study proposed this alteration may impact gene interactions involved in transcription and cardiac development (Brassington AM et al. Am J Hum Genet. 2003;73:74-85; Waldron L et al. Dev Cell. 2016;36(3):262-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001855258 SCV002121458 uncertain significance Aortic valve disease 2 2023-09-25 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects TBX5 function (PMID: 26859351). 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) performed at Invitae indicates that this missense variant is not expected to disrupt TBX5 protein function. ClinVar contains an entry for this variant (Variation ID: 518540). This missense change has been observed in individual(s) with Holt-Oram syndrome (PMID: 12789647). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs377625550, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 261 of the TBX5 protein (p.Ser261Cys).
Fulgent Genetics, Fulgent Genetics RCV002483702 SCV002794105 uncertain significance Holt-Oram syndrome 2021-08-05 criteria provided, single submitter clinical testing
Baylor Genetics RCV002483702 SCV003835462 uncertain significance Holt-Oram syndrome 2022-09-29 criteria provided, single submitter clinical testing

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