ClinVar Genomic variation as it relates to human health

The p.T201M variant (also known as c.602C>T), located in coding exon 6 of the TPM1 gene, results from a C to T substitution at nucleotide position 602. The threonine at codon 201 is replaced by methionine, an amino acid with similar properties. This variant has been detected in a large kindred with dilated cardiomyopathy; however, while it was detected in a number of affected individuals, it was also detected in several unaffected family members (Dorsch LM et al. Int J Cardiol, 2021 01;323:251-258). This variant has also been detected in individuals from dilated cardiomyopathy cohorts; however, clinical details were limited (van Spaendonck-Zwarts KY et al. Eur J Heart Fail, 2013 Jun;15:628-36; Mazzarotto F et al. Circulation, 2020 02;141:387-398). In vitro assays from one group indicated this variant may impact calcium transients; however, the physiological relevance of this finding is unclear. And cardiac biopsies from variant carriers demonstrated abnormal sarcomere structure (Dorsch LM et al. Int J Cardiol, 2021 01;323:251-258). 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.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 201 of the TPM1 protein (p.Thr201Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 23349452, 31983221, 32882290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181668). 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: 32882290). For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces threonine with methionine at codon 201 in the actin binding domain of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study using transfected cardiomyocytes has shown that this variant may impact calcium transients (PMID: 32882290). This variant has been reported in multiple unrelated individuals affected with dilated cardiomyopathy (PMID: 23349452, 31983221, 32746448, 32882290). In one large family, this variant has been shown to segregate with disease in 12 affected individuals ranging in age from 21 to 84 years; this variant was also present in 16 unaffected carriers, ranging in age from 3 to 56 years. By the age of 60, 55% of individuals carrying this variant in this family were diagnosed with dilated cardiomyopathy (PMID: 32882290). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

PM2, PS3, PS4mod

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; Functional studies demonstrate p.(T201M) results in reduced calcium transient; however, the correlation with these findings to the clinical phenotype is unclear (PMID: 32882290); This variant is associated with the following publications: (PMID: 35029218, 34681814, 31983221, 32746448, 36264615, 23349452, 32882290)