ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5870G>A (p.Arg1957Gln) (rs199473331)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058812 SCV000235552 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing The R1958Q variant of uncertain significance in the SCN5A gene has been reported previously in one individual with LQTS, and was absent from 1,500 control alleles (Tester et al., 2005). However, a subsequent study by the same group identified the R1958Q variant in 3/8,975 control individuals and classified as a polymorphism (Kapplinger et al., 2015). Additionally, the R1958Q variant is observed in 27/272,604 (0.01%) global alleles in large population cohorts (Lek et al., 2016). The R1958Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000058812 SCV000333788 uncertain significance not provided 2015-08-28 criteria provided, single submitter clinical testing
Invitae RCV001087675 SCV000545048 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000987194 SCV001136443 benign Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color RCV001185308 SCV001351489 likely benign Arrhythmia 2019-10-09 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058812 SCV000090332 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:15840476;PMID:19841300;PMID:20129283;PMID:22378279).
CSER _CC_NCGL, University of Washington RCV000148844 SCV000190585 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000212995 SCV000280481 uncertain significance not specified 2015-02-02 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.Arg1958Gln (R1958Q; c.5873 G>A) in the SCN5A gene: The Arg1958Gln variant has been reported previously in one patient with LQTS (Tester et al. 2005). Variation at nearby residues has been reported in association with diseases including Brugada, LQT3, SIDS, and atrial fibrillation: A1949S; V1951L; V1951M; I1968S (UniProtKB; IRCCS Fondazione Salvatore Maugeri database). This is a non-conservative amino acid change, resulting in the replacement of a basic, positively-charged arginine with a polar, neutral glutamine. The arginine at this location varies in 11 of 40 mammalian species sequenced, and it is normally a glutamine in 5 of them. The adjacent residues similarly vary across species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign”. According to 1000 Genomes, SIFT characterizes this variant as “tolerated”. In total the variant has been seen in 4 out of >7258 published controls or individuals from publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient is of Mexican ancestry.) It is present in 2/1729 African-American individuals (and 0/3400 Caucasians) in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). Another variant at the same codon—p.Arg1958Trp—was found in 1/3380 Caucasian individuals. The variant is also present in 1 individual of African descent from 1000 Genomes (http://browser.1000genomes.org/index.htm), which contains 70 individuals of Mexican ancestry from Los Angeles, as of May 13, 2012. There is no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). The variant was observed in 1 published control: Tester et al. (2005) did not find it in 829 control individuals, but in a subsequent study from the same group Kapplinger et al. (2010) did find the variant in 1/1300 control individuals (649 Caucasian and 651 non-white “blacks, Asians, Hispanics, and others”); the individual with the variant was African American. GeneDx did not report controls.

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