ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.5851G>T (p.Val1951Leu) (rs41315493)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171770 SCV000055297 likely benign Atrial fibrillation; Brugada syndrome 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041632 SCV000065328 benign not specified 2012-03-19 criteria provided, single submitter clinical testing p.Val1951Leu in Exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 6.5% (6/92) of chromosomes from a population in the dbSNP database (; rs4 1315493).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000041632 SCV000114839 benign not specified 2013-07-05 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000041632 SCV000257779 benign not specified 2015-07-01 criteria provided, single submitter clinical testing
Invitae RCV000058811 SCV000260075 benign not provided 2019-03-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000041632 SCV000306552 likely benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000245882 SCV000318649 benign Cardiovascular phenotype 2015-08-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000058811 SCV000843725 benign not provided 2017-10-18 criteria provided, single submitter clinical testing
Color RCV000776120 SCV000910998 benign Arrhythmia 2018-03-19 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000058811 SCV000987699 likely benign not provided criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852961 SCV000995710 benign Cardiomyopathy; Long QT syndrome 2019-06-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000058811 SCV001153855 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030444 SCV000053113 benign Long QT syndrome 2015-01-08 no assertion criteria provided clinical testing Variant Summary: c.5848G>T is a missense variant that occurrs at a non-conserved position, and 5/5 in silico tools predict benign outcome of this variant. The observed allele frequency in an ethnically diverse set of control chromosomes is 102/24,730 (1/242; 0.41%; 2 homozgotes reported); this frequency is significantly higher than the maximal expected allele frequency of 1/48,000 for a pathogenic SCN5A variant for LQTS/SCD or 1/6,000 for BrS. The ExAC population reports the variant in 477/11,174 (1/23; 4.27%) Latino chromosomes, with 6 homozygotes. These allele frequencies strongly suggest that the variant is benign. Further support of a benign outcome is a reported Korean family (Shin et al, 2003) where this variant did not cosegregate with disease, and a sudden cardiac death patient whom also carried another potentially pathogenic variant in the KCNE1 gene (Tester et al 2012). Functional studies results are in conflict, but suggest that the variant may have a modifying effect dependent upon the presence of other SCN5A variants. Most in vitro studies have shown that the variant has no significant effect on in vitro function when in isolation. V1951L did not exhibit an overt LQT3-like phenotype or an overt loss of function phenotype, therefore its involvement in the settings of either LQT3 or Brugada syndrome is not substantiated. Furthermore, although the authors reported other "significant functional disturbances" , the results and conclusions of these findings are not applicable to the mechanism of action, and physiologic consequences or presentation of disease (i.e., LQT3 or Brugada). Collectively, although this variant may play a role in the context of complex or oligogenic alleles, in isolation there is no evidence to suggest that it significantly impairs SCN5A function, several reputable sources classify the variant as benign, and the significantly higher oberseved allele frequency compared to the maximimal expected allele frequency of a pathogenic SCN5A variant indicate that the in vivo consequence of this variant is, indeed, benign.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058811 SCV000090331 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10807545;PMID:11901046;PMID:15851227;PMID:16379539;PMID:17210839;PMID:18426444;PMID:19841300;PMID:21109022;PMID:20129283;PMID:15992732;PMID:17210841;PMID:22378279).
CSER _CC_NCGL, University of Washington RCV000148837 SCV000190578 likely benign Brugada syndrome 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000157493 SCV000207238 likely benign Pulmonary valve stenosis (rare); Ventricular tachycardia 2014-08-15 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000041632 SCV000280480 uncertain significance not specified 2015-03-26 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val1951Leu (c.5851G>T) in the SCN5A gene. This variant has been reported in published literature. Priori et al (2004) reported the presence of the variant in one Caucasian individual who had a Brugada syndrome diagnosis. It was also reported in a case of SIDS (Arnestad et al 2007). In vitro studies have been conflicting, with some reporting an abnormal biophysical phenotype (Wang er al 2008) and others reporting normal function (Tan et al 2005). Arnestad et al commented that this variant could exhibit ethnic-dependent phenotype expression (2007). A nonpolar, neutral Valine is replaced with a nonpolar, neutral Leucine at position 1951 in the SCN5A gene. The change does not affect the net charge of the polypeptide. This codon is not well conserved across species. In 2004, Darbar et al sequenced the SCN5A coding region of 378 individuals with Atrial fibrillation (alone or in association with another cardiac condition), they identified one Caucasian individual with atrial fibrillation and HCM who harbored a variant in the same codon (p.Val1951Met). In this patient’s family the variant did co segregate with phenotype in the patient’s father, paternal grandmother and 2 siblings. Priori et al (2004) report this variant was not found in 400 Caucasian presumably healthy controls. Genedx did not find the variant in 200 Caucasian and African American controls. However, the p.Val1951Leu variant has been reported in 6.7% of normal Hispanics (Ackerman et al 2005). Darbar et al (2008) reported that the p.Val1951Leu variant was observed in 7 out of 720 presumably healthy controls of both Caucasian and African American descent. In addition, Kapplinger et al (2010) reported that the p.Val1951Leu variant is found in highest percentage in Hispanic controls, then Asian, African America and “other” presumably healthy controls. They classified this variant as a polymorphism. Given these data, the impact of this variant on arrhythmic risk is unclear. It is possible that it is a common variant (i.e. >5%) in several ancestral groups and that it was identified in the published cases of SIDS and Brugada because of its prevalence, not because of its pathogenicity.

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