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

gnomAD frequency: 0.00001  dbSNP: rs199476321

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000024581	SCV000209336	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as this variant alters the binding affinity of tropomyosin for actin (Bai et al., 2013; Sequeira et al., 2013; Gupte et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12860912, 20965760, 23508784, 23071391, 18533079, 27532257, 25524337, 21823217, 23700264, 22112859, 21835320, 30297972, 31308319, 32882290, 30240712, 34011823, 25548289, 30847666, 35626289)
Invitae	RCV000232738	SCV000285670	pathogenic	Hypertrophic cardiomyopathy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the TPM1 protein (p.Met281Thr). This variant is present in population databases (rs199476321, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 18533079, 20965760, 21835320, 22112859, 25524337, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31885). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TPM1 function (PMID: 25548289). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000618291	SCV000739941	pathogenic	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.M281T pathogenic mutation (also known as c.842T>C), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 842. The methionine at codon 281 is replaced by threonine, an amino acid with some similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), and co-segregation was reported in affected family members in some cases (Van Driest SL, Circulation 2003 Jul; 108(4):445-51; Olivotto I, Mayo Clin. Proc. 2008 Jun; 83(6):630-8; Coppini R, J. Am. Coll. Cardiol. 2014 Dec; 64(24):2589-600; Otsuka H, Circ. J. 2012; 76(2):453-61; Walsh R et al. Genet. Med., 2017 02;19:192-203; Tran Vu MT et al. Circ. J., 2019 Aug;83:1908-1916). This variant was also reported in a child with restrictive cardiomyopathy, who had an additional TPM1 variant detected in trans; her mother and maternal uncle were asymptomatic carriers for only p.M281T, although the uncle reportedly showed mild left ventricular hypertrophy (Dorsch LM et al. Int J Cardiol, 2020 Sep;[Epub ahead of print]). In addition, studies suggest this alteration has an impact on protein function, but the clinical relevance of these findings is uncertain (Gupte TM, J. Biol. Chem. 2015 Mar; 290(11):7003-15; Dorsch LM et al. Int J Cardiol, 2020 Sep;[Epub ahead of print]). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 Center for Human Genetics Tuebingen	RCV000024581	SCV000892133	likely pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	TPM1: PM2, PM5, PP3, PS3:Supporting, PS4:Supporting
KTest Genetics, KTest	RCV001594374	SCV001499981	likely pathogenic	Dilated cardiomyopathy 1Y		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149577	SCV003837753	likely pathogenic	Cardiomyopathy	2021-09-13	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (TPM1)	RCV000024581	SCV000045890	not provided	not provided	2012-04-15	no assertion provided	curation
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154219	SCV000203874	uncertain significance	not specified	2016-11-30	flagged submission	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Clinical Genetics, Academic Medical Center	RCV000024581	SCV001923479	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000024581	SCV001957811	pathogenic	not provided		no assertion criteria provided	clinical testing