rs199476310
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The ENST00000403994.9(TPM1):c.275T>C(p.Ile92Thr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I92M) has been classified as Pathogenic.
Frequency
Consequence
ENST00000403994.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.275T>C | p.Ile92Thr | missense_variant | 3/10 | ENST00000403994.9 | NP_001018005.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.275T>C | p.Ile92Thr | missense_variant | 3/10 | 1 | NM_001018005.2 | ENSP00000385107 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 11, 2014 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 92 of the TPM1 protein (p.Ile92Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20215591, 21483645, 27532257, 33906374; Invitae). ClinVar contains an entry for this variant (Variation ID: 31891). 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 disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 29496559). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2023 | The p.I92T variant (also known as c.275T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 275. The isoleucine at codon 92 is replaced by threonine, an amino acid with similar properties. This variant has been detected in identical twins with pediatric-onset dilated cardiomyopathy (DCM), and was also detected in relatives reported to have DCM (Hershberger RE et al. Circ Cardiovasc Genet, 2010 Apr;3:155-61;Rampersaud E et al. Prog. Pediatr. Cardiol., 2011 Jan;31:39-47). This variant has also been reported in cohorts referred for DCM genetic testing; however, details were limited and reports may overlap (Walsh R et al. Genet. Med., 2017 02;19:192-203; Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). One study reported this variant may impact protein function (liwinska M et al. Biochim Biophys Acta Proteins Proteom, 2018 Apr;1866:558-568). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at