ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.187G>A (p.Ala63Thr)

dbSNP: rs1064796782
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478328 SCV000573851 uncertain significance not provided 2021-05-14 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV001851267 SCV002185841 uncertain significance Hypertrophic cardiomyopathy 2024-04-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 63 of the TPM1 protein (p.Ala63Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TPM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 424074). 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. This variant disrupts the p.Ala63 amino acid residue in TPM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8774330, 12900417, 15059934, 15479242, 20161772, 30022097; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics RCV003343856 SCV004051545 uncertain significance Cardiovascular phenotype 2023-07-14 criteria provided, single submitter clinical testing The p.A63T variant (also known as c.187G>A), located in coding exon 2 of the TPM1 gene, results from a G to A substitution at nucleotide position 187. The alanine at codon 63 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV001851267 SCV004831404 uncertain significance Hypertrophic cardiomyopathy 2023-04-24 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 63 of the TPM1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TPM1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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