rs104894504

chr15-63057028-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001018005.2(TPM1):c.284T>C(p.Val95Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TPM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 15-63057028-T-C is Pathogenic according to our data. Variant chr15-63057028-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63057028-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.284T>C	p.Val95Ala	missense_variant	3/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.284T>C	p.Val95Ala	missense_variant	3/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2014	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2023	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. -

Hypertrophic cardiomyopathy 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 02, 2001	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2020

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) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	26
Dann	Benign	0.97
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;T;T;T;T;T;T;T;D;T;T;T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D
Sift4G	Benign	0.49	T;T;T;T;T;T;T;.;.;T;T;.;T;T;T
Polyphen		0.030, 0.70, 0.033, 0.95	.;.;B;P;.;.;.;B;.;.;.;.;.;P;.
Vest4		0.89
MutPred		0.80		.;.;.;Loss of stability (P = 0.1641);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.85
gMVP		0.99

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: rs104894504; hg19: chr15-63349227;