ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.842T>C (p.Met281Thr) (rs199476321)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154219 SCV000203874 uncertain significance not specified 2016-11-30 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000024581 SCV000209336 likely pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The M281T variant that is likely pathogenic was identified in the TPM1 gene. This variant has previously been reported multiple times in association with HCM (Van Driest et al., 2003; Olivotto et al., 2008; Olivotto et al., 2011; Otsuka et al., 2012; Sequeira et al., 2013; Coppini et al., 2014; Walsh et al., 2017). This variant has also been identified, both independently and in conjunction with additional cardiogenetic variants, in multiple other unrelated individuals referred for HCM genetic testing at GeneDx. The M281T variant is not observed in large population cohorts (Lek et al., 2016). This 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies demonstrate that the M281T variant alters the binding affinity of tropomyosin for actin (Bai et al., 2013; Sequeira et al., 2013; Gupte et al., 2014).
Invitae RCV000232738 SCV000285670 pathogenic Hypertrophic cardiomyopathy 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 281 of the TPM1 protein (p.Met281Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 21835320, 22112859, 25524337, 18533079, 27532257, Invitae) and left ventricular non-compaction (PMID: 20965760). Experimental studies have shown that this variant changes TPM1 binding affinity for actin (PMID: 25548289). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618291 SCV000739941 likely pathogenic Cardiovascular phenotype 2019-09-30 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622737 SCV000740435 likely pathogenic Primary familial hypertrophic cardiomyopathy 2016-07-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000024581 SCV000892133 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (TPM1) RCV000024581 SCV000045890 not provided not provided 2012-04-15 no assertion provided curation

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