Submissions for variant NM_001018005.2(TPM1):c.284T>C (p.Val95Ala) (rs104894504)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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	2012-06-11	criteria provided, single submitter	clinical testing	The Val95Ala mutation in the TPM1 gene has been reported previously in association with HCM. Karibe A et al. (2001) reported that the Val95Ala mutation, which was absent from 200 control individuals, co-segregates with HCM in a large family where all 14 individuals with the mutation were affected. Within this family, 11 additional individuals died due to cardiomyopathy suggesting a poor prognosis, despite a mild disease presentation. Although Val95Ala results in a conservative amino acid substitution of one non-polar amino acid with another, the substitution occurs at a position that is highly conserved in vertebrates throughout evolution. Functional study data indicate Val95Ala increases thin filament Ca2+ sensitivity and alters the rate of myosin cycling. Another mutation in a nearby codon (Ile92Thr) has been reported in association with DCM (Hershberger R et al., 2010), further supporting the functional importance of this region of the protein. Val95Ala was not observed in up to 400 alleles in control individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphism in these populations. In summary, Val95Ala in the TPM1 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Ambry Genetics	RCV000619092	SCV000740262	likely pathogenic	Cardiovascular phenotype	2017-12-14	criteria provided, single submitter	clinical testing	Strong segregation with disease (lod >3 = >10 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae	RCV000211870	SCV001230836	pathogenic	Hypertrophic cardiomyopathy	2019-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine with alanine at codon 95 of the TPM1 protein (p.Val95Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family (PMID: 11136687) and has been observed in an individual affected with dilated cardiomyopathy (PMID: 29540472). ClinVar contains an entry for this variant (Variation ID: 12457). This variant has been reported to affect TPM1 protein function (PMID: 11136687, 21295541, 21320446, 22187526, 29496559). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013273	SCV000033520	pathogenic	Familial hypertrophic cardiomyopathy 3	2001-01-02	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (TPM1)	RCV000013273	SCV000045881	not provided	Familial hypertrophic cardiomyopathy 3	2012-04-15	no assertion provided	curation