Submissions for variant NM_000335.5(SCN5A):c.246C>G (p.Asp82Glu)

dbSNP: rs747643709

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842580	SCV001342083	uncertain significance	Cardiac arrhythmia	2020-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 82 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/237766 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	RCV000998028	SCV001986470	uncertain significance	not provided	2019-09-13	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
Invitae	RCV000998028	SCV002317871	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	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 tolerated. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 82 of the SCN5A protein (p.Asp82Glu). This variant is present in population databases (rs747643709, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 809451). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000998028	SCV002502066	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000998028	SCV002542039	uncertain significance	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002454248	SCV002738265	uncertain significance	Cardiovascular phenotype	2021-01-08	criteria provided, single submitter	clinical testing	The p.D82E variant (also known as c.246C>G), located in coding exon 1 of the SCN5A gene, results from a C to G substitution at nucleotide position 246. The aspartic acid at codon 82 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002497311	SCV002776570	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	2021-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411943	SCV004111771	uncertain significance	SCN5A-related condition	2022-10-31	criteria provided, single submitter	clinical testing	The SCN5A c.246C>G variant is predicted to result in the amino acid substitution p.Asp82Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38674553-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.