ClinVar Miner

Submissions for variant NM_006514.4(SCN10A):c.4639G>T (p.Val1547Leu)

gnomAD frequency: 0.00009  dbSNP: rs377492327
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523387 SCV000620758 uncertain significance not provided 2023-10-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29247119)
Labcorp Genetics (formerly Invitae), Labcorp RCV000687974 SCV000815569 uncertain significance Brugada syndrome 2023-08-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 451988). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). This variant is present in population databases (rs377492327, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1547 of the SCN10A protein (p.Val1547Leu). 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 SCN10A protein function. 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.
Ambry Genetics RCV002341229 SCV002639877 uncertain significance Cardiovascular phenotype 2023-01-14 criteria provided, single submitter clinical testing The p.V1547L variant (also known as c.4639G>T), located in coding exon 26 of the SCN10A gene, results from a G to T substitution at nucleotide position 4639. The valine at codon 1547 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in a sudden death cohort; however, details were limited (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This amino acid position is well 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.

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