ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.253G>T (p.Val85Leu) (rs730881156)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544344 SCV000623800 uncertain significance Hypertrophic cardiomyopathy 2019-06-25 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 85 of the TPM1 protein (p.Val85Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with dilated cardiomyopathy (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Val85 amino acid residue in TPM1. Other variant(s) that disrupt this residue have been observed in individuals with TPM1-related conditions (PMID: 29121657), which suggests that this may be a clinically significant amino acid residue. 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.
Integrated Genetics/Laboratory Corporation of America RCV001193551 SCV001362452 uncertain significance not specified 2019-10-29 criteria provided, single submitter clinical testing Variant summary: TPM1 c.253G>T (p.Val85Leu) 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 was absent in 251460 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.253G>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786233 SCV000924974 uncertain significance not provided 2017-05-08 no assertion criteria provided provider interpretation We have seen this variant in one patient with DCM. Testing was performed at Invitae. Given the lack of case data and absence in general population databases, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been seen in any cases of DCM or cardiomyopathy. There are no published cases. Per the lab report: "A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275)." The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 35x.

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