ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1891-8G>A (rs12720064)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000151791 SCV000514540 likely benign not specified 2017-06-01 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 RCV000151791 SCV000920190 uncertain significance not specified 2017-10-10 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.1891-8G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/270732 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000422 (10/23702). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, two clinical diagnostic laboratories classified this variant as likely benign and one other lab classified it as uncertain significance, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS)-possibly benign until additional information becomes available.
Invitae RCV000456628 SCV000557146 likely benign Brugada syndrome 2017-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151791 SCV000200247 uncertain significance not specified 2017-11-06 criteria provided, single submitter clinical testing The c.1891-8G>A variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 10/23702 of African chromosomes by the Genome Aggregation Database (gnomAD,; d bSNP rs12720064). This variant is located in the 3' splice region. Computational tools do not suggest an impact to splicing. However, this information is not pr edictive enough to rule out pathogenicity. In summary, the clinical significance of the c.1891-8G>A variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richar ds 2015).

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