ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.4531C>T (p.Arg1511Trp) (rs137854602)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058688 SCV000235490 likely pathogenic not provided 2015-08-24 criteria provided, single submitter clinical testing The R1512W variant has been reported in association with Brugada syndrome and it has also been identified in a healthy control individual (Rook M et al., 1999; Deschenes I et al., 2000; Meregalli et al., 2009, Ackerman et al., 2004). Deschenes et al. reported the R1512W variant in a 43-year-old man who experienced his first syncopal attack while bicycling at slow speed; the ECG strongly suggested Brugada syndrome. Meregalli et al. (2009) reported R1512W was identified in two unrelated probands with Brugada syndrome or progressive cardiac conduction disease and was absent in 200 control alleles. In addition, this variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1512W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Missense mutations in nearby residues (G1502S, S1503P, K1505N, P1506T, I1521K) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), further supporting the functional importance of this region of the protein. However, Ackerman et al. (2004) identified R1512W in one control individual of Hispanic descent. Furthermore, functional studies performed by Deschenes et al. (2000) and Rook et al. (1999) have conflicting findings. Deschenes et al. (2000) demonstrated R1512W results in loss of function, a slowing of inactivation and recovery from inactivation in mammalian cells; thus reducing the number of channels available for opening after each cardiac cycle. Meanwhile, Rook et al. (1999) found R1512W resulted in a gain of function in xenopus oocytes, leading to an increase in inward sodium current during the action potential upstroke; time for activation and inactivation were not significantly affected. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000222521 SCV000272416 uncertain significance not specified 2019-01-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1512Trp variant in SCN5A has been reported in 7 individuals with features of arrhythmia, sudden death, Brugada syndrome and/or LQTS (Rook 1999, Deschênes 2000, Meregalli 2009, Cheng 2011, Crotti 2012, Chiang 2015) and in 1 individual with infantile onset of LV dysfunction (LMM data). It has been identified in 9/33552 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs137854602). This variant is present in ClinVar (Variation ID: 9380). In vitro functional studies provide some evidence that the variant may impact protein function (Rook 1999, Deschênes 2000, Zheng 2016). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg1512Trp variant is uncertain.
Center for Medical Genetics Ghent,University of Ghent RCV000009977 SCV000299258 likely pathogenic Brugada syndrome 1 2016-01-01 criteria provided, single submitter clinical testing
Invitae RCV000456844 SCV000545007 uncertain significance Brugada syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1512 of the SCN5A protein (p.Arg1512Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs137854602, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with Brugada syndrome (PMID: 10690282, 15851227, 26111534, 20486126, 22840528, 25650408), several individuals affected with sudden unexplained nocturnal death syndrome (PMID: 15851227, 20110800, 24529773), and in several healthy control individuals (PMID: 15851227, 20129283, 19841300). ClinVar contains an entry for this variant (Variation ID: 9380). Experimental studies have shown that this missense change causes a slowing of the kinetics of inactivation and recovery from inactivation in the channel (PMID: 10690282, 10727653). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000009977 SCV000996193 likely pathogenic Brugada syndrome 1 2018-08-30 criteria provided, single submitter clinical testing This variant has been previously reported by multiple clinical labs as pathogenic or likely pathogenic according to the ClinVar database. One clinical lab reports p.Arg1512Trp as a variant of uncertain significance. Additionally, there multiple reports in the literature of the variant in patients diagnosed with Brugada Syndrome and arrhythmias (PMID: 10690282, 10727653, 19251209, 20110800, 26111534, 27281089). This variant was identified in a healthy adult in one publication (PMID: 15851227). Functional studies characterizing the effect of the variant on protein function demonstrates altered channel gating dynamics relative to the reference allele. Deschenes et al. demonstrated that p.Arg1512Trp results in loss of function, producing a slowing of both inactivation and recovery from inactivation (PMID: 10727653). Rook et al. found p.Arg1512Trp resulted in moderate kinetic alterations including a negative voltage shift of steady-state activation and inactivation curves (PMID: 10690282). More recently, Zheng et al. identified a de novo p.Arg1512Trp variant in a 38 year old Chinese patient with tachypnea and sudden unexplained noctural death (SUNDS)(PMID: 27281089). These authors also demonstrated a more deleterious effect of the variant under slightly acidic conditions (pH 7.0 versus pH 7.4). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/246090) and thus is presumed to be rare. The p.Arg1512Trp variant is a non-conservative amino acid substitution predicted to be damaging by multiple in silico tools and the amino acid residue is highly conserved among eukaryotes. Based on the available evidence, the c.4534C>T (p.Arg1512Trp) variant is classified as likely pathogenic.
Color RCV001185020 SCV001351146 uncertain significance Arrhythmia 2019-07-27 criteria provided, single submitter clinical testing
OMIM RCV000009977 SCV000030198 pathogenic Brugada syndrome 1 1999-12-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058688 SCV000090208 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10690282;PMID:10727653;PMID:15851227;PMID:19251209;PMID:19841300;PMID:20129283).
Blueprint Genetics RCV000157490 SCV000207235 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-07-18 no assertion criteria provided clinical testing

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