Submissions for variant NM_006514.4(SCN10A):c.827G>A (p.Cys276Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1251019283

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001318895	SCV001509615	uncertain significance	Brugada syndrome	2020-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 276 of the SCN10A protein (p.Cys276Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. 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. 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. This variant has not been reported in the literature in individuals with SCN10A-related conditions. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics	RCV002431911	SCV002680169	uncertain significance	Cardiovascular phenotype	2022-02-02	criteria provided, single submitter	clinical testing	The p.C276Y variant (also known as c.827G>A), located in coding exon 6 of the SCN10A gene, results from a G to A substitution at nucleotide position 827. The cysteine at codon 276 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051893	SCV005685195	uncertain significance	Episodic pain syndrome, familial, 2	2024-06-04	criteria provided, single submitter	clinical testing	The SCN10A c.827G>A (p.Cys276Tyr) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters. This variant is only observed on 1/251,274 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to Na_v1.8 function. Additionally, another variant in a highly related gene in the paralogous amino acid, SCN1A p.Cys277Arg, has been described in individuals with Dravet syndrome and is considered pathogenic (ClinVar Variation ID: 2203200). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.