ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1715C>A (p.Ala572Asp) (rs36210423)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000151795 SCV000235296 benign not specified 2016-12-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000230669 SCV000291783 benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000244195 SCV000317847 benign Cardiovascular phenotype 2015-10-01 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000264595 SCV000444119 likely benign Sick sinus syndrome 1, autosomal recessive 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000143951 SCV000444124 likely benign Paroxysmal familial ventricular fibrillation 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 Inc RCV000438831 SCV000843709 likely benign not provided 2018-04-18 criteria provided, single submitter clinical testing
Color RCV000776127 SCV000911065 benign Arrhythmia 2018-03-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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
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 Paroxysmal familial ventricular fibrillation 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

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