ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.3951G>A (p.Glu1317=) (rs769473892)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000248843 SCV000515374 likely benign not specified 2017-01-16 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.
Integrated Genetics/Laboratory Corporation of America RCV000248843 SCV000920191 benign not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: SCN5A c.3954G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 3.3e-05 in 267386 control chromosomes (gnomAD). The observed variant frequency is approximately 1-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. To our knowledge, no occurrence of c.3954G>A in individuals affected with Cardiomyopathy and/or Arrhythmia, and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000701318 SCV000830113 uncertain significance Brugada syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change affects codon 1318 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. This variant is present in population databases (rs769473892, ExAC 0.007%). This variant has not been reported in the literature in individuals affected with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 257441). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
PreventionGenetics RCV000248843 SCV000306545 likely benign not specified criteria provided, single submitter clinical testing

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