ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1993G>A (p.Ala665Thr) (rs756474485)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771948 SCV000904901 uncertain significance Arrhythmia 2018-10-20 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DI and DII of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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. This variant has been reported in an infant with sudden death (PMID: 29907895). This variant has also been identified in 18/276636 chromosomes (12/30782 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000766788 SCV000235592 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The A665T variant has not been published as pathogenic or been reported as benign to our knowledge. The A665T variant is observed in 18/276636 (0.0065%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, the A665T 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. Finally, although another missense variant at this same residue (A665S) has been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000536248 SCV000637095 uncertain significance Brugada syndrome 2018-06-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 665 of the SCN5A protein (p.Ala665Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs756474485, ExAC 0.02%). This variant has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201579). 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 C55"). In summary, this variant has uncertain impact on SCN5A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183175 SCV000272408 uncertain significance not specified 2015-06-11 criteria provided, single submitter clinical testing The p.Ala665Thr variant in SCN5A has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of the p.Ala665Thr variant is uncertain.

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