rs199476306

Positions:

• chr15-63044100-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_001018005.2(TPM1):​c.188C>T​(p.Ala63Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 7.54

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Tropomyosin alpha-1 chain (size 283) in uniprot entity TPM1_HUMAN there are 61 pathogenic changes around while only 1 benign (98%) in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TPM1. . Gene score misZ 2.8677 (greater than the threshold 3.09). Trascript score misZ 3.9402 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.
• PP5: Variant 15-63044100-C-T is Pathogenic according to our data. Variant chr15-63044100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31877.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr15-63044100-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.188C>T	p.Ala63Val	missense_variant	2/10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.188C>T	p.Ala63Val	missense_variant	2/10	1	NM_001018005.2	ENSP00000385107.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2018	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). -

Hypertrophic cardiomyopathy 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

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 -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 23, 2022

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). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Benign	0.035
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
ClinPred		0.93	D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199476306; hg19: chr15-63336299;