ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.602C>T (p.Thr201Met) (rs730881141)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159374 SCV000209320 uncertain significance not provided 2015-11-30 criteria provided, single submitter clinical testing The T201M variant of uncertain significance in the TPM1 gene has been reported in association with DCM (van Spaedonck-Zwarts et al., 2013). van Spaedonck-Zwarts (2013) reported the T201M variant was identified in two individuals with familial DCM and was absent from 300 ethnically matched control alleles. In addition, the NHLBI Exome Sequencing Project reports T201M was not observed in approximately 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. The T201M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position where amino acids with properties similar to Threonine are tolerated across species. Consequently, in silico analysis predicts that this variant is probably damaging to the protein structure/function. Nevertheless, only two missense variants in nearby residues (E192K, Q210R) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
Invitae RCV000687999 SCV000815595 uncertain significance Hypertrophic cardiomyopathy 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 201 of the TPM1 protein (p.Thr201Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 23349452). ClinVar contains an entry for this variant (Variation ID: 181668). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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