ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.548C>T (p.Ala183Val) (rs397516376)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036342 SCV000059994 uncertain significance not specified 2015-10-07 criteria provided, single submitter clinical testing The p.Ala183Val variant in TPM1 has been identified by our laboratory in 1 indiv idual with HCM and was absent from large population studies. Computational predi ction tools and conservation analysis suggest that the p.Ala183Val variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala183Val variant is uncertain.
GeneDx RCV000766949 SCV000209314 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TPM1 gene. The A183V variant has been reported in association with HCM (Lopes et al., 2015; Walsh et al., 2017; Burns et al., 2017); however, additional clinical information was not provided. The A183V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, the A183V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000538013 SCV000623805 uncertain significance Hypertrophic cardiomyopathy 2017-06-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 183 of the TPM1 protein (p.Ala183Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TPM1-related disease. ClinVar contains an entry for this variant (Variation ID: 43424). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000620344 SCV000740025 uncertain significance Cardiovascular phenotype 2016-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000538013 SCV000996347 likely pathogenic Hypertrophic cardiomyopathy 2017-07-25 criteria provided, single submitter research The TPM1 Ala183Val has previously been reported in 6 individuals with HCM (Walsh R, et al 2017;SCV000209314 - GeneDx personal communication). We have identified this variant in 3 probands of European ethnicity; 2 with no family history of disease and 1 with an affected sibling who also harbours this variant. The TPM1 Ala183Val variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). In silico tools, MutationTaster, PolyPhen-2 and SIFT predict this variant the be deleterious. Based on this information we classify this variant as "likely pathogenic".

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