ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.797A>G (p.Lys266Arg) (rs371934474)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154863 SCV000204545 uncertain significance not specified 2014-01-17 criteria provided, single submitter clinical testing The Lys266Arg variant in TPM1 has not been previously reported in any other fami lies with cardiomyopathy, but has been identified in 1/4406 African American chr omosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /). Computational analyses (biochemical amino acid properties, conservation, Ali gnGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an imp act to the protein. Additional information is needed to fully assess the clinica l significance of this variant.
Invitae RCV000475992 SCV000547689 uncertain significance Hypertrophic cardiomyopathy 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 266 of the TPM1 protein (p.Lys266Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs371934474, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 178148). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624321 SCV000740437 uncertain significance Left ventricular noncompaction 2017-07-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154863 SCV000920324 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: TPM1 c.797A>G (p.Lys266Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 277096 control chromosomes, predominantly within the African subpopulation at a frequency of 0.00083 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPM1 causing Cardiomyopathy phenotype (7.5e-05), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.797A>G has been reported in the literature in two individuals affected with Cardiomyopathy (Walsh 2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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