Submissions for variant NM_006514.4(SCN10A):c.3425G>A (p.Arg1142His)

gnomAD frequency: 0.00006  dbSNP: rs200584416

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001766985	SCV001989970	uncertain significance	not provided	2022-07-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882861	SCV002174670	uncertain significance	Brugada syndrome	2023-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1142 of the SCN10A protein (p.Arg1142His). This variant is present in population databases (rs200584416, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN10A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1306032). 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 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	RCV002458578	SCV002615545	likely benign	Cardiovascular phenotype	2022-06-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801044	SCV005423280	uncertain significance	not specified	2024-10-15	criteria provided, single submitter	clinical testing	Variant summary: SCN10A c.3425G>A (p.Arg1142His) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 1614052 control chromosomes, predominantly in the African or African American subpopulation at a frequency of 0.00016 in 75004 control chromosomes (gnomAD v4). Although this frequency is not significantly higher than estimated for a pathogenic variant in SCN10A causing SCN10A-Related Disorders, this data suggests the variant may be benign. To our knowledge, no occurrence of c.3425G>A in individuals affected with SCN10A-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1306032). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.