ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2708T>C (p.Met903Thr)

gnomAD frequency: 0.00001  dbSNP: rs1341909190
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001840986 SCV001353927 uncertain significance Cardiac arrhythmia 2023-12-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DII of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV001876191 SCV002146706 uncertain significance Brugada syndrome 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 903 of the SCN5A protein (p.Met903Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 925323). 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. 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.
Ambry Genetics RCV003284025 SCV004007572 uncertain significance Cardiovascular phenotype 2023-03-19 criteria provided, single submitter clinical testing The p.M903T variant (also known as c.2708T>C), located in coding exon 15 of the SCN5A gene, results from a T to C substitution at nucleotide position 2708. The methionine at codon 903 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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