Submissions for variant NM_000335.5(SCN5A):c.486C>T (p.Tyr162=)

gnomAD frequency: 0.00267  dbSNP: rs45489099

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151807	SCV000200273	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Tyr162Tyr in Exon 05 of SCN5A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 0.9% (28/3212) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs45489099).
Eurofins Ntd Llc (ga)	RCV000151807	SCV000231242	likely benign	not specified	2014-09-25	criteria provided, single submitter	clinical testing
Invitae	RCV000713146	SCV000557123	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621518	SCV000737251	likely benign	Cardiovascular phenotype	2016-02-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Athena Diagnostics	RCV000713146	SCV000843723	benign	not provided	2018-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842476	SCV000913814	benign	Cardiac arrhythmia	2018-06-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001144575	SCV001305186	benign	Long QT syndrome 3	2019-04-23	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001144576	SCV001305187	uncertain significance	Brugada syndrome 1	2019-04-23	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	RCV001144577	SCV001305188	likely benign	Progressive familial heart block, type 1A	2019-04-23	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001144578	SCV001305189	benign	Sick sinus syndrome 1	2019-04-23	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001144579	SCV001305190	likely benign	Ventricular fibrillation, paroxysmal familial, type 1	2019-04-23	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001146500	SCV001307249	benign	Dilated cardiomyopathy 1E	2019-04-23	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151807	SCV001363136	benign	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.486C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 248802 control chromosomes. The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.486C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile) at our laboratory providing supporting evidence for a benign role. 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 benign (n=3)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000713146	SCV001846524	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486670	SCV004239676	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000151807	SCV001924972	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000713146	SCV001929690	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000713146	SCV001952707	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000713146	SCV001964208	likely benign	not provided		no assertion criteria provided	clinical testing