Submissions for variant NM_000335.5(SCN5A):c.52C>T (p.Arg18Trp)

gnomAD frequency: 0.00006  dbSNP: rs199473044

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058764	SCV000235313	likely benign	not provided	2020-08-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32048431, 28988457, 28600387, 25904541, 20129283, 15840476, 25351510, 19862833, 23805106, 29728395)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212988	SCV000540277	uncertain significance	not specified	2016-04-25	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: ExAC: 0.2% (32/16508) South Asian
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058764	SCV000557143	likely benign	not provided	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619162	SCV000738183	benign	Cardiovascular phenotype	2021-05-27	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623091	SCV000740427	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2017-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842382	SCV000913714	likely benign	Cardiac arrhythmia	2018-10-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000987246	SCV001136496	benign	Brugada syndrome 1	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987246	SCV001307372	uncertain significance	Brugada syndrome 1	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146621	SCV001307373	uncertain significance	Sick sinus syndrome 1	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146622	SCV001307374	uncertain significance	Dilated cardiomyopathy 1E	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146623	SCV001307375	uncertain significance	Progressive familial heart block, type 1A	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146624	SCV001307376	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001146625	SCV001307377	uncertain significance	Long QT syndrome 3	2019-05-08	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058764	SCV000090284	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:15840476;PMID:19841300;PMID:20129283).
Blueprint Genetics	RCV000157474	SCV000207219	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2014-10-14	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000212988	SCV000280477	benign	not specified	2011-07-18	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg18Trp (c.52C>T) in the SCN5A gene Given the frequency in ancestry-matched unselected individuals and the very weak case data we consider this variant to be likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Tester et al (2005) observed the variant in 1 of 541 cases. This publication is a compendium of variants identified in cases referred to Dr. Ackerman's research lab for long QT genetic testing. No individual clinical or segregation data was provided. Of note when considering this paper, it is likely that ~25% of patients in this cohort did not actually have long QT syndrome (based on the reported yield). The variant was reported online in 39 of 59,815 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 21, 2015). The highest frequency was in 32 of 8254. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.