Submissions for variant NM_000335.5(SCN5A):c.1715C>A (p.Ala572Asp)

dbSNP: rs36210423

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151795	SCV000200252	likely benign	not specified	2015-08-12	criteria provided, single submitter	clinical testing	p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs36210423) and was re ported at slightly lower frequencies in control cohorts across multiple studies investigating the genetic cause of LQTS and related clinical entities (Mank-Seym our 2006, Arnestad 2007, Albert 2008, Tester 2010). There is a possibility that the p.Ala572Asp variant may have a minor impact on protein function (Albert 2008 , Tester 2010, Koval 2012); however, these in vitro assays may not accurately re present biological function. Although a modifying role in disease cannot be full y excluded, this variant is likely benign.
GeneDx	RCV000438831	SCV000235296	benign	not provided	2020-04-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23008441, 22378279, 20403459, 12820704, 27243970, 27153395, 27287068, 27930701, 18452873, 28781330, 29672598, 29214556, 28988457, 29032884, 32880476)
Invitae	RCV000438831	SCV000291783	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244195	SCV000317847	benign	Cardiovascular phenotype	2015-10-01	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.
Illumina Laboratory Services, Illumina	RCV000264595	SCV000444119	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001094811	SCV000444120	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). 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	RCV000360867	SCV000444121	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000268589	SCV000444122	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000326049	SCV000444123	likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000143951	SCV000444124	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000438831	SCV000510889	likely benign	not provided	2017-01-03	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Athena Diagnostics	RCV000438831	SCV000843709	likely benign	not provided	2018-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842295	SCV000911065	benign	Cardiac arrhythmia	2018-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000151795	SCV000920198	benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing	Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies show the variant could have a gain-of-function implication (Ortiz-Bonin_2016), an affect on recovery time (Albert_2008), or acts like wild type SCN5A, although in the context of a certain genotype such as the SCN5A polymorphism H588R moderate dysfunction was observed (Tester_2010). Overall, the authors indicate that the variant is not associated with the LQTS phenotype. This variant was found in 1486/279922 control chromosomes (23 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.038676 (997/25778). This frequency is about 387 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Multiple publications have cited the variant of interest in affected individuals. One family reported by Paulussen_2003 found the variant to be in two unaffected family members, with the proband carrying the variant and another pathogenic KCNQ1 variant, V254M, while Ortiz-Bonnin_2016 reported an affected family member that did not carry the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, based on reports of co-occurrence with a pathogenic variant in another gene, lack of co-segregation with disease phenotype, and an unexpectedly high frequency in controls, this variant is classified as benign, although the possibility of a modifier effect in certain genetic backgrounds cannot be ruled out.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852965	SCV000995714	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2017-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000438831	SCV002496801	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	SCN5A: BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002504971	SCV002808373	benign	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	2021-09-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486630	SCV004239655	benign	Cardiomyopathy	2023-03-03	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058447	SCV000089967	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:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Blueprint Genetics	RCV000143951	SCV000188831	likely benign	Ventricular fibrillation, paroxysmal familial, type 1	2014-08-29	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157480	SCV000207225	likely benign	Left ventricular noncompaction cardiomyopathy	2014-08-29	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157481	SCV000207226	likely benign	Cardiac arrest	2014-08-29	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000438831	SCV001743547	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000151795	SCV001925392	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000151795	SCV001932901	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000438831	SCV001955001	likely benign	not provided		no assertion criteria provided	clinical testing