Submissions for variant NM_000335.5(SCN5A):c.1967C>T (p.Pro656Leu)

gnomAD frequency: 0.00115  dbSNP: rs41313681

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000058469	SCV000055302	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041608	SCV000065304	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	Pro656Leu in exon 13 of SCN5A: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (14/3728) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs41313681). Pro656Leu in exon 13 of SCN5A (r s41313681; allele frequency = 0.4%, 14/3728) **
Eurofins Ntd Llc (ga)	RCV000041608	SCV000225947	benign	not specified	2015-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000058469	SCV000235394	likely benign	not provided	2020-10-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19841300, 20129283, 15851227, 25854863, 23861362, 26746457)
Invitae	RCV000058469	SCV000557117	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000058469	SCV000700022	likely benign	not provided	2016-05-23	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.1967C>T (p.Pro656Leu) variant involves the alteration of a mildly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 48/121480 control chromosomes at a frequency of 0.0003951, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. However, it has been reported being detected in the control cohorts, further supporting benign classification (Ackerman_2004, Kapa_2009, and Kapplinger_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as Likely Benign until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001841597	SCV000913815	likely benign	Cardiac arrhythmia	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147411	SCV001308234	benign	Dilated cardiomyopathy 1E	2017-04-27	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	RCV001147412	SCV001308235	benign	Progressive familial heart block, type 1A	2017-04-27	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	RCV001147413	SCV001308236	benign	Sick sinus syndrome 1	2017-04-27	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	RCV001147414	SCV001308237	likely benign	Brugada syndrome 1	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001147415	SCV001308238	benign	Long QT syndrome 3	2017-04-27	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	RCV001147416	SCV001308239	likely benign	Ventricular fibrillation, paroxysmal familial, type 1	2017-04-27	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.
PreventionGenetics, part of Exact Sciences	RCV004541213	SCV004775977	likely benign	SCN5A-related disorder	2021-01-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Ambry Genetics	RCV004017337	SCV004849274	likely benign	Cardiovascular phenotype	2018-10-15	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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058469	SCV000089989	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300;PMID:20129283).