Submissions for variant NM_000335.5(SCN5A):c.1705C>T (p.Arg569Trp)

gnomAD frequency: 0.00001  dbSNP: rs199473576

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001842293	SCV001356356	uncertain significance	Cardiac arrhythmia	2023-05-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 569 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). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 25904541). This variant has been reported in an individual affected with long QT syndrome (PMID: 25904541) and in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has been identified in 2/249008 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	RCV002223784	SCV001485562	uncertain significance	not provided	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 569 of the SCN5A protein (p.Arg569Trp). This variant is present in population databases (rs199473576, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 67680). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541). 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	RCV002223784	SCV002502484	uncertain significance	not provided	2021-10-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504970	SCV002815266	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	2021-10-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003227633	SCV003925622	uncertain significance	Dilated cardiomyopathy 1E	2023-04-18	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS4_SUP, PM2_SUP, PM5_SUP, PP3
All of Us Research Program, National Institutes of Health	RCV001842293	SCV004832954	uncertain significance	Cardiac arrhythmia	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 569 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). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 25904541). This variant has been reported in an individual affected with long QT syndrome (PMID: 25904541) and in an individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has been identified in 2/249008 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	RCV000058444	SCV000089964	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
PreventionGenetics, part of Exact Sciences	RCV004734616	SCV005345307	uncertain significance	SCN5A-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The SCN5A c.1705C>T variant is predicted to result in the amino acid substitution p.Arg569Trp. This variant has been reported in at least one individual with long QT syndrome, and functional studies showed that this variant does not impact protein function (Table S3, Kapplinger et al. 2009. PubMed ID: 19716085; Tables S1 and S4, Kapplinger et al. 2015. PubMed ID: 25904541). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.