rs104894504
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001018005.2(TPM1):c.284T>C(p.Val95Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.284T>C | p.Val95Ala | missense_variant | 3/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.284T>C | p.Val95Ala | missense_variant | 3/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 06, 2014 | The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2023 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12457). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 11136687, 29540472). It has also been observed to segregate with disease in related individuals. - |
Hypertrophic cardiomyopathy 3 Pathogenic:1Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 02, 2001 | - - |
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2020 | Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 12457; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect as this variant results in increased thin filament Ca2+ sensitivity and alters the rate of myosin cycling (Karibe et al., 2001); This variant is associated with the following publications: (PMID: 11136687, 29540472, 22187526, 21320446, 21295541) - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 25, 2020 | The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 284. The valine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration was reported to segregate with hypertrophic cardiomyopathy in a multi-generation family with reduced penetrance (Karibe A et al. Circulation, 2001 Jan;103:65-71). This variant has also been detected in a dilated cardiomypathy cohort (Hazebroek MR et al. Circ Heart Fail. 2018 03;11(3):e004682). In vitro assays suggested that this mutant would affect protein structure and function (Karibe A et al. Circulation, 2001 Jan;103:65-71; Bai F et al. Biophys. J., 2011 Feb;100:1014-23; Mathur MC et al. Biochem. Biophys. Res. Commun., 2011 Mar;406:74-8; Wang F et al. J. Biomed. Biotechnol., 2011 Dec;2011:435271). This variant was not reported in population-based 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at