ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.572_573delinsTT (p.Ala191Val) (rs730881154)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159404 SCV000209350 uncertain significance not provided 2014-05-06 criteria provided, single submitter clinical testing The c.572_573delCCinsTT variant has not been published as a variant, nor has it been reported as a benign polymorphism to our knowledge. The c.572_573delCCinsTT variant results in a deletion of CC and insertion of TT, maintaining the reading frame and leading to an Alanine residue being replaced with a Valine residue at position 191 (A191V). The A191V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The c.572_573delCCinsTT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense variants in nearby residues (L185R, E192K, T201M) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000628953 SCV000749861 uncertain significance Hypertrophic cardiomyopathy 2017-09-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 191 of the TPM1 protein (p.Ala191Val). The alanine residue is weakly 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: 181681). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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