Submissions for variant NM_000335.5(SCN5A):c.1735G>A (p.Gly579Arg)

gnomAD frequency: 0.00005  dbSNP: rs199473128

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454856	SCV000540283	uncertain significance	not specified	2016-08-11	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported as a novel longQT variant in 2005 - proband count not provided. Also reported in 1 ostensibly healthy adult. ClinVar: P by GeneDx
Invitae	RCV000058450	SCV000545056	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the SCN5A protein (p.Gly579Arg). This variant is present in population databases (rs199473128, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944). ClinVar contains an entry for this variant (Variation ID: 67686). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454856	SCV000700021	likely benign	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1735G>A (p.Gly579Arg) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-05 in 252230 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1735G>A has been reported in the literature in at-least one individual affected with Long QT Syndrome (example, Napolitano_2005) and in at-least one individual with Left ventricular noncompation (LVNC) who harbored a co-occuring likely pathogenic variant in the MYH7 gene and a pathogenic variant in the DMD gene (Alimohamed_2021) supporting possible alternative molecular basis of disease. These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000987222	SCV001136471	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842296	SCV001351108	uncertain significance	Cardiac arrhythmia	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 579 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 long QT syndrome (PMID: 16414944). This variant has also been identified in 21/280032 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058450	SCV000089970	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:20129283;PMID:16414944;PMID:19841300).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058450	SCV001744837	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000058450	SCV001923377	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058450	SCV001968994	uncertain significance	not provided		no assertion criteria provided	clinical testing