Submissions for variant NM_000335.5(SCN5A):c.3497G>A (p.Cys1166Tyr)

gnomAD frequency: 0.00001  dbSNP: rs993780673

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842114	SCV001735326	uncertain significance	Cardiac arrhythmia	2023-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 1167 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31392 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.
GeneDx	RCV001751783	SCV001987503	uncertain significance	not provided	2019-05-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV001751783	SCV002181323	uncertain significance	not provided	2023-08-05	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1171846). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1167 of the SCN5A protein (p.Cys1167Tyr).
Fulgent Genetics, Fulgent Genetics	RCV002506644	SCV002814534	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-08-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842114	SCV004815146	uncertain significance	Cardiac arrhythmia	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 1167 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/31392 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.