Submissions for variant NM_001018005.2(TPM1):c.188C>T (p.Ala63Val)

dbSNP: rs199476306

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229431	SCV000285666	pathogenic	Hypertrophic cardiomyopathy	2022-06-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TPM1 function (PMID: 12006676, 12900417, 15059934, 15479242, 20161772). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 31877). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 8774330, 30022097; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 63 of the TPM1 protein (p.Ala63Val).
GeneDx	RCV000024573	SCV000589543	likely pathogenic	not provided	2018-01-12	criteria provided, single submitter	clinical testing	The A63V likely pathogenic variant in the TPM1 gene has been reported in multiple individuals with HCM (Nakajima-Taniguchi et al., 1995; Yamauchi-Takihara et al., 1996; Lopes et al., 2015). Additionally, A63V is classified as a likely pathogenic variant by another clinical laboratory in ClinVar (SCV000285666.2; Landrum et al., 2016). The A63V variant is not observed in large population cohorts (Lek et al., 2016). Although the A63V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, functional studies show that the A63V variant destabilizes the tropomyosin protein and results in muscle cell dysfunction (Michele et al., 2002; Heller et al., 2003; Hilario et al., 2004).
Ambry Genetics	RCV000619544	SCV000740245	uncertain significance	Cardiovascular phenotype	2021-08-09	criteria provided, single submitter	clinical testing	The c.188C>T (p.A63V) alteration is located in exon 2 (coding exon 2) of the TPM1 gene. This alteration results from a C to T substitution at nucleotide position 188, causing the alanine (A) at amino acid position 63 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470718	SCV002766862	pathogenic	Hypertrophic cardiomyopathy 3	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes, p.(Ala63Pro) and p.(Ala63Thr), have been reported as VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as a VUS, but more commonly as likely pathogenic, and observed in at least eleven unrelated individuals with hypertrophic cardiomyopathy (HCM) (ClinVar, PMID: 24170035, PMID: 8523464, PMID: 8774330, PMID: 29398688, PMID: 30022097, PMID: 25351510). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated within a family with HCM (PMID: 24170035), but also observed in several unaffected relatives (personal communication). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been proven to result in reduced effectiveness in regulating ATPase activity and heat instability (PMID: 15479242). Additionally, when transfected into rat cardiac myocytes this variant resulted in slowed cell relengthening (PMID: 15059934). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Leiden Muscular Dystrophy (TPM1)	RCV000024573	SCV000045879	not provided	not provided	2012-04-15	no assertion provided	curation