Submissions for variant NM_000335.5(SCN5A):c.1247A>G (p.Tyr416Cys)

dbSNP: rs372395294

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182965	SCV000235362	uncertain significance	not provided	2017-02-08	criteria provided, single submitter	clinical testing	The Y416C variant of uncertain significance has been identified in the SCN5A gene. The Y416C variant has previously been published in association with Brugada syndrome in a 62 year old male with ventricular fibrillation induced by electrical stimulation and a family history of sudden death (Nagase et al., 2008); however, segregation data was not provided. The Y416C variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y416C 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. Missense variants in nearby residues (V411M, A413T, A413E) have been reported in the Human Gene Mutation Database in association with Long QT syndrome (LQTS) (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the Y416C variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000470340	SCV000541076	pathogenic	Familial isolated arrhythmogenic right ventricular dysplasia		criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001842895	SCV001346704	uncertain significance	Cardiac arrhythmia	2022-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 416 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). This variant has been identified in 1/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000182965	SCV005834208	uncertain significance	not provided	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 416 of the SCN5A protein (p.Tyr416Cys). This variant is present in population databases (rs372395294, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 28341781). ClinVar contains an entry for this variant (Variation ID: 201449). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 34219138). 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.