rs199476312
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_001018005.2(TPM1):āc.515T>Cā(p.Ile172Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I172M) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018005.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPM1 | NM_001018005.2 | c.515T>C | p.Ile172Thr | missense_variant | 5/10 | ENST00000403994.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPM1 | ENST00000403994.9 | c.515T>C | p.Ile172Thr | missense_variant | 5/10 | 1 | NM_001018005.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Other:1
Likely pathogenic, flagged submission | clinical testing | Blueprint Genetics | Nov 02, 2017 | - - |
not provided, no classification provided | curation | Leiden Muscular Dystrophy (TPM1) | Apr 15, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 31, 2018 | A variant of uncertain significance has been identified in the TPM1 gene. The I172T variant was reported as novel in one patient with HCM and a family history of HCM as well as sudden cardiac death (Van Driest et al., 2003). However, this study cohort was screened only for thin filament variants. Subsequently, Van Driest et al. (2004) reported I172T in an individual with HCM who also harbored an MYBPC3 variant, presumably the same patient from the 2003 study due to cohort overlap. Additionally, one functional study suggests that this variant does not impact protein function (Gupte et al., 2015), whereas a more recent functional study suggests this variant may lead to a milder phenotype (Matyushenko et al., 2017). Nevertheless, the I172T 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. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Primary familial hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 21, 2017 | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 26, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TPM1 function (PMID: 25548289, 27983818). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 31879). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12860912, 15519027, 33673806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 172 of the TPM1 protein (p.Ile172Thr). - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 15, 2023 | This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 33673806, 33495597, 23299917, 33495596, 33673806, 12860912, 15519027). This variant is present in 1/251434 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant may result in a mild phenotype; however, additional studies are needed (PMID: 25548289, 27983818). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at