ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544344 SCV000623800 uncertain significance Hypertrophic cardiomyopathy 2017-03-07 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) and has not been reported in the literature in individuals with a TPM1-related disease. Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic and dilated cardiomyopathy (PMID: 27532257). 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). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of 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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