rs199476321
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001018005.2(TPM1):c.842T>C(p.Met281Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250772Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135550
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461634Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727084
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:5Other:1
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Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as this variant alters the binding affinity of tropomyosin for actin (PMID: 23700264, 23508784, 25548289); 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, 30847666, 35626289, 36964972, 37652022, 37466024, 33495597, 37946154, 33495596, 24793961, 36555368, 25548289) -
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TPM1: PM2, PM5, PP3, PS3:Supporting, PS4:Supporting -
PP2, PP3, PS3, PS4_moderate -
Hypertrophic cardiomyopathy Pathogenic:3
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; internal data). 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. -
The p.Met281Thr variant in TPM1 has been reported in at least 13 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 3 affected relatives from 3 families (Van Driest 2003 PMID: 12860912, Olivotto 2008 PMID: 18533079, Otsuka 2012 PMID: 22112859, Sequeira 2013 PMID: 23508784, Coppini 2014 PMID:255224337, Tran Vu 2019 PMID: 31308319, LMM data). It has also been reported in 1 individual with DCM and in the compound heterozygous state with another TPM1 variant in 1 individual with RCM (Dorsch 2021 PMID: 32882290, Nguyen 2021 PMID: 34011823). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID 31885) and has been identified in 0.0008% (1/113468) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Met281Thr variant may impact protein function (Sequeira 2013 PMID: 23508784, Gupte 2015 PMID: 25548289, Dorsch 2021 PMID: 32882290). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3, PS3_Supporting. -
This missense variant replaces methionine with threonine at codon 281 in the alternate splicing region of the TPM1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. In-vitro functional studies using isolated protein have shown that this variant causes an increased sensitivity to calcium, increased thermal stability, altered myosin interaction with thin filament (PMID: 25548289, 36555368). Additionally, functional studies using patient-derived tissue samples have shown that this variant causes loss of sarcomere striations and loss of intact cardiac muscle fibers as well as increased calcium sensitivity (PMID: 23508784, 32882290). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 18533079, 22112859, 24793961, 25524337, 23508784, 27532257, 30847666, 31308319, 33495596, 33495597) and in one individual affected with restrictive cardiomyopathy (PMID: 32882290). This variant has been identified in 1/250772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Cardiomyopathy Pathogenic:1
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Dilated cardiomyopathy 1Y Pathogenic:1
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Primary familial hypertrophic cardiomyopathy Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
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). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at