ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.844C>T (p.Arg282Cys) (rs199473082)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058850 SCV000090370 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Center for Medical Genetics Ghent,University of Ghent RCV000240636 SCV000299255 likely pathogenic Brugada syndrome 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000182949 SCV000235346 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing The R282C variant of uncertain significnance in the SCN5A gene has been reported in one individual referred for Brugada syndrome genetic testing (Kapplinger et al., 2010); however, additional clinical and segregation information was not provided. Additionally, while this variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx, segregation data suggests that this variant is not segregating with disease in one family. Nevertheless, the R282C variant is not observed in large population cohorts (Lek et al., 2016). The R282C 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-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, a missense variant in the same residue (R282H) has been reported in the Human Gene Mutation Database in association with an SCN5A-related disorder (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000781844 SCV000920201 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.844C>T (p.Arg282Cys) variant involves the alteration of a conserved nucleotide and is located in the ion transport domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/33556 control chromosomes at a frequency of 0.0000298, which does not exceed the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667). This variant has been reported in at least one BrS patient. In addition, multiple clinical diagnostic laboratories have classified this variant as likely pathogenic. Variant involving the same codon R282H (c.845G>A) has also been reported in BrS-affected individuals suggesting the functional importance of this codon. Taken together, this variant is classified as VUS-possibly pathogenic.
Invitae RCV000058850 SCV000819463 uncertain significance Brugada syndrome 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 282 of the SCN5A protein (p.Arg282Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for testing for Brugada syndrome (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 68047). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg282 amino acid residue in SCN5A have been observed in affected individuals (PMID: 11901046, 15828879, 20129283). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
SIB Swiss Institute of Bioinformatics RCV000240636 SCV000803522 uncertain significance Brugada syndrome 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Brugada syndrome 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

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