rs104894502

chr15-63060915-A-Gchr15-63060915-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001018005.2(TPM1):c.539A>G(p.Glu180Gly) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E180K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM1 NM_001018005.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.32

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 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001018005.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-63060914-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1002513.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, TPM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 15-63060915-A-G is Pathogenic according to our data. Variant chr15-63060915-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63060915-A-G is described in Lovd as [Pathogenic]. Variant chr15-63060915-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2	c.539A>G	p.Glu180Gly	missense_variant	5/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9	c.539A>G	p.Glu180Gly	missense_variant	5/10	1	NM_001018005.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 3 Pathogenic:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 03, 1994	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2021

Multiple published functional studies demonstrate increased tropomyosin calcium-sensitivity and perturbation of normal contractile kinetics (Bing et al., 1997; Bai et al., 2011; Borovikov et al., 2011; Ly and Lehrer, 2012); transgenic animal models demonstrate diastolic dysfunction, hypertrophy, and fibrosis (Prabhakar et al., 2001; Michele et al., 2002; Gaffin et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21320446, 27878731, 12169652, 22155441, 21295541, 9245729, 22794249, 22958892, 22187526, 10900175, 8205619, 25525159, 11136687, 20161772, 25241052, 22796693, 21047515, 8327508, 26109583, 22789852, 21376702, 11603924, 17313334, 29636697, 21840315, 27535533, 31535252) -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 03, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu180 amino acid residue in TPM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11044437; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM1 function (PMID: 10900175, 11603924, 22789852). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12455). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8205619). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 180 of the TPM1 protein (p.Glu180Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;H;H;H;H;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D
Polyphen		1.0, 0.68	.;.;D;P;.;.;.;D;.;.;.;.;.;D;.;.
Vest4		0.92
MutPred		0.77		.;.;.;Gain of helix (P = 0.1736);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894502; hg19: chr15-63353114;