Submissions for variant NM_001018005.2(TPM1):c.725C>T (p.Ala242Val)

dbSNP: rs397516387

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001237828	SCV001410608	pathogenic	Hypertrophic cardiomyopathy	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 242 of the TPM1 protein (p.Ala242Val). This variant is present in population databases (rs397516387, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 24691700, 27532257, 30847666, 34935411; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43437). 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. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV001588845	SCV001815800	likely pathogenic	Dilated cardiomyopathy 1Y	2020-07-17	criteria provided, single submitter	clinical testing	The heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene substitutes a well conserved Alanine for Valine at amino acid 242/285 (exon 8/10). This variant is absent from gnomAD(v3.0) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Deleterious (Provean; score:-3.3) and Damaging (SIFT; score:0.00) to the function of the canonical transcript. This variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:43437), and has been identified in several individuals in the literature with left ventricular non-compaction [PMID:24691700; PMID:30371277; PMID:28798025] and dilated cardiomyopathy [PMID:27532257; PMID:24503780; PMID:30847666]. Given its absence in population databases, in silico prediction of damaging effect to protein function, and its observation in several affected individuals in the literature, the heterozygous c.725C>T (p.Ala242Val) variant identified in the TPM1 gene is reported as Likely Pathogenic.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319174	SCV003932421	likely pathogenic	Primary dilated cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343608	SCV004074904	likely pathogenic	Cardiovascular phenotype	2023-08-25	criteria provided, single submitter	clinical testing	The p.A242V variant (also known as c.725C>T), located in coding exon 8 of the TPM1 gene, results from a C to T substitution at nucleotide position 725. The alanine at codon 242 is replaced by valine, an amino acid with similar properties. This variant has been detected in several unrelated individuals with dilated cardiomyopathy (DCM) and/or left ventricular noncompaction cardiomyopathy (LVNC), including a reported de novo occurrence and reported segregation with disease in a family (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Tian T et al. Heart Vessels, 2015 Mar;30:258-64; Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854; van der Meulen MH et al. Circ Genom Precis Med, 2022 Oct;15:e002981; Meshkov AN et al. Front Cardiovasc Med, 2023 May;10:1205787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036357	SCV000060009	uncertain significance	not specified	2020-08-12	flagged submission	clinical testing	The p.Ala242Val variant in TPM1 has been identified in one individual with LVNC (Tian 2015 PMID: 24691700), one individual with DCM and segregated with disease in one family member, but was also present in one unaffected family member (LMM data). This variant has also been identified in 1 of 113742 European alleles in gnomAD. Computational predictors predict that the variant is damaging. The residue is entirely conserved and no species harbor the variant amino acid. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3
Clinical Genetics, Academic Medical Center	RCV001699184	SCV001926060	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001699184	SCV001963059	likely pathogenic	not provided		no assertion criteria provided	clinical testing