Submissions for variant NM_006514.4(SCN10A):c.4118T>G (p.Met1373Arg)

gnomAD frequency: 0.00001  dbSNP: rs1131691400

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493315	SCV000582048	uncertain significance	not provided	2017-12-29	criteria provided, single submitter	clinical testing	The c.4118 T>G variant in the SCN10A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.4118 T>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.4118 T>G may create a cryptic splice donor site in exon 23, which may supplant the natural donor site. However, in the absence of RNA/functional studies, the actual effect of the c.4118 T>G change in this individual is unknown. If c.4118 T>G does not alter splicing, it will result in the M1373R missense change. The M1373R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.4118 T>G as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242314	SCV001415394	uncertain significance	Brugada syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1373 of the SCN10A protein (p.Met1373Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with atrioventricular block (PMID: 31977013). ClinVar contains an entry for this variant (Variation ID: 429470). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN10A function (PMID: 31977013). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.