ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.188C>T (p.Ala63Val) (rs199476306)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229431 SCV000285666 likely pathogenic Hypertrophic cardiomyopathy 2016-11-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 63 of the TPM1 protein (p.Ala63Val). 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 been reported in an individual and their parent, both affected with hypertrophic cardiomyopathy (HCM) (PMID: 8774330). Currently, there is insufficient evidence to conclude whether this variant segregates with disease or not. ClinVar contains an entry for this variant (Variation ID: 31877). Experimental studies have shown that this missense change disrupts TPM1 protein stability (PMID: 12900417, 15479242) and slows down the relaxation time in adult rat cardiac myocytes (PMID: 15059934, 20161772). In summary, this variant is a rare missense change that is absent in the general population, has been reported in one HCM family, and has been shown to disrupt protein function. In the absence of further genetic data, at this point, it has been classified as Likely Pathogenic.
GeneDx RCV000024573 SCV000589543 likely pathogenic not provided 2018-01-12 criteria provided, single submitter clinical testing The A63V likely pathogenic variant in the TPM1 gene has been reported in multiple individuals with HCM (Nakajima-Taniguchi et al., 1995; Yamauchi-Takihara et al., 1996; Lopes et al., 2015). Additionally, A63V is classified as a likely pathogenic variant by another clinical laboratory in ClinVar (SCV000285666.2; Landrum et al., 2016). The A63V variant is not observed in large population cohorts (Lek et al., 2016). Although the A63V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, functional studies show that the A63V variant destabilizes the tropomyosin protein and results in muscle cell dysfunction (Michele et al., 2002; Heller et al., 2003; Hilario et al., 2004).
Ambry Genetics RCV000619544 SCV000740245 uncertain significance Cardiovascular phenotype 2017-11-15 criteria provided, single submitter clinical testing Insufficient evidence;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Leiden Muscular Dystrophy (TPM1) RCV000024573 SCV000045879 not provided not provided 2012-04-15 no assertion provided curation

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