Submissions for variant NM_001018005.2(TPM1):c.284T>C (p.Val95Ala)

dbSNP: rs104894504

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211870	SCV000203873	pathogenic	Hypertrophic cardiomyopathy	2014-10-06	criteria provided, single submitter	clinical testing	The Val95Ala variant in TPM1 has been reported in 1 Spanish-American individual with HCM and segregated with disease in >10 affected family members (Karibe 200 1). It was absent from large population studies. In vitro functional studies ind icate this variant may impact protein function (Karibe 2001, Mathur 2011, Bai 20 11, Wang 2011); however, in vitro assays may not accurately represent biological function. Valine (Val) at position 95 is highly conserved in mammals and across evolutionarily distant species and the change to alanine (Ala) was predicted to be pathogenic using a computational tool clinically validated by our laboratory . This tool's pathogenic prediction is estimated to be correct 94% of the time ( Jordan 2011). In summary, this variant meets our criteria to be classified as pa thogenic for HCM in an autosomal dominant manner (http://www.partners.org/person alizedmedicine/LMM) based upon segregation studies, absence from controls, and f unctional evidence.
GeneDx	RCV000159356	SCV000209302	pathogenic	not provided	2020-01-09	criteria provided, single submitter	clinical testing	Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 12457; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a damaging effect as this variant results in increased thin filament Ca2+ sensitivity and alters the rate of myosin cycling (Karibe et al., 2001); This variant is associated with the following publications: (PMID: 11136687, 29540472, 22187526, 21320446, 21295541)
Ambry Genetics	RCV000619092	SCV000740262	likely pathogenic	Cardiovascular phenotype	2020-09-25	criteria provided, single submitter	clinical testing	The p.V95A variant (also known as c.284T>C), located in coding exon 3 of the TPM1 gene, results from a T to C substitution at nucleotide position 284. The valine at codon 95 is replaced by alanine, an amino acid with similar properties. This alteration was reported to segregate with hypertrophic cardiomyopathy in a multi-generation family with reduced penetrance (Karibe A et al. Circulation, 2001 Jan;103:65-71). This variant has also been detected in a dilated cardiomypathy cohort (Hazebroek MR et al. Circ Heart Fail. 2018 03;11(3):e004682). In vitro assays suggested that this mutant would affect protein structure and function (Karibe A et al. Circulation, 2001 Jan;103:65-71; Bai F et al. Biophys. J., 2011 Feb;100:1014-23; Mathur MC et al. Biochem. Biophys. Res. Commun., 2011 Mar;406:74-8; Wang F et al. J. Biomed. Biotechnol., 2011 Dec;2011:435271). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae	RCV000211870	SCV001230836	pathogenic	Hypertrophic cardiomyopathy	2023-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 95 of the TPM1 protein (p.Val95Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12457). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 11136687, 29540472). It has also been observed to segregate with disease in related individuals.
OMIM	RCV000013273	SCV000033520	pathogenic	Hypertrophic cardiomyopathy 3	2001-01-02	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (TPM1)	RCV000013273	SCV000045881	not provided	Hypertrophic cardiomyopathy 3	2012-04-15	no assertion provided	curation