ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.62G>T (p.Arg21Leu) (rs730881151)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000168980 SCV000209344 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing The R21L variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The R21L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R21L 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. In addition, this substitution occurs at a position that is conserved across species. Moreover, missense mutations in nearby residues (K15N, A22T) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201492 SCV000256207 likely pathogenic Familial hypertrophic cardiomyopathy 3 criteria provided, single submitter clinical testing
Ambry Genetics RCV000244434 SCV000318597 uncertain significance Cardiovascular phenotype 2019-08-20 criteria provided, single submitter clinical testing The p.R21L variant (also known as c.62G>T), located in coding exon 1 of the TPM1 gene, results from a G to T substitution at nucleotide position 62. The arginine at codon 21 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) (Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Mendes de Almeida R et al. PLoS ONE, 2017 Aug;12:e0182946). 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.
Invitae RCV000524610 SCV000623810 uncertain significance Hypertrophic cardiomyopathy 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 21 of the TPM1 protein (p.Arg21Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs730881151, ExAC 0.01%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 28138913, 28797094). However, in one of these individuals a pathogenic allele was also identified in MYBPC3. ClinVar contains an entry for this variant (Variation ID: 181678). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Blueprint Genetics RCV000168980 SCV000927905 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000524610 SCV000995152 uncertain significance Hypertrophic cardiomyopathy 2018-11-22 criteria provided, single submitter clinical testing

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