Submissions for variant NM_000335.5(SCN5A):c.1852C>T (p.Leu618Phe)

gnomAD frequency: 0.00178  dbSNP: rs45488304

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154842	SCV000204524	likely benign	not specified	2015-06-05	criteria provided, single submitter	clinical testing	p.Leu618Phe in exon 12 of SCN5A: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (59/9220) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs45488304).
GeneDx	RCV000058456	SCV000235387	likely benign	not provided	2021-01-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22378279, 24055113, 25637381, 20129283, 26332594, 11997281, 24631775, 14760488, 28491593)
Invitae	RCV000058456	SCV000291784	benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618998	SCV000735635	likely benign	Cardiovascular phenotype	2018-11-29	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	RCV000058456	SCV000843711	benign	not provided	2018-02-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842299	SCV000913700	benign	Cardiac arrhythmia	2018-10-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154842	SCV000918193	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1852C>T (p.Leu618Phe) 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 damaging effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 216 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 a benign polymorphism found primarily in populations of African origin. The variant, c.1852C>T, has been reported in the literature in individuals affected with sudden unexplained death (SUD)( Wang_2014 ), Brugada syndrome (Amin_2009), atrial fibrillation (Darbar_2008), and long QT syndrome (Tester_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy, Brugada syndrome, atrial fibrillation, Long QT, or SCD. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Yang_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as Benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000058456	SCV000987524	likely benign	not provided		criteria provided, single submitter	clinical testing
Mendelics	RCV000987220	SCV001136469	benign	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058456	SCV002049132	likely benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058456	SCV000089976	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:11997281;PMID:14760488;PMID:15840476;PMID:19841300;PMID:20129283;PMID:12673799;PMID:22378279).
CSER _CC_NCGL, University of Washington	RCV000148843	SCV000190584	likely benign	Long QT syndrome, drug-associated	2014-06-01	no assertion criteria provided	research