ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.944T>C (p.Leu315Pro) (rs199473564)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766782 SCV000235350 uncertain significance not provided 2014-05-14 criteria provided, single submitter clinical testing p.Leu315Pro (CTG>CCG): c.944 T>C in exon 8 of the SCN5A gene (NM_198056.2) The L315P variant in the SCN5A gene has been reported in a single patient with Brugada syndrome (Kapplinger J et al., 2010). The L315P variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the L315P variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. However, another missense mutation in a nearby residue (K317N) has been reported in association with Brugada syndrome supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000058862 SCV000261247 uncertain significance Brugada syndrome 2015-10-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 315 of the SCN5A protein (p.Leu315Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (rs199473564, ExAC no frequency). This variant has been reported in an individual referred for Brugada testing. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 68058). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000182953 SCV000540280 uncertain significance not specified 2016-06-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 BrS proband. ClinVar: GeneDx classifies as VUS.
Ambry Genetics RCV000620872 SCV000738095 uncertain significance Cardiovascular phenotype 2017-09-12 criteria provided, single submitter clinical testing Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058862 SCV000090382 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.

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