rs104894505

Variant names:

• chr15-63044072-G-A
• rs104894505
• NM_001018005.2:c.160G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_001018005.2(TPM1):​c.160G>A​(p.Glu54Lys) 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 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:4 U:1 O:1
• Conservation: PhyloP100: 9.56

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 Likely_pathogenic. Variant got 7 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 the TPM1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 42 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 2.8677 (below the threshold of 3.09). Trascript score misZ: 3.9402 (above the threshold of 3.09). GenCC associations: The gene is linked to dilated cardiomyopathy, left ventricular noncompaction, hypertrophic cardiomyopathy, hypertrophic cardiomyopathy 3, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1Y.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 15-63044072-G-A is Pathogenic according to our data. Variant chr15-63044072-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12458.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr15-63044072-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2	c.160G>A	p.Glu54Lys	missense_variant	Exon 2 of 10	ENST00000403994.9	NP_001018005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9	c.160G>A	p.Glu54Lys	missense_variant	Exon 2 of 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:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Nov 01, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E54K variant in the TPM1 gene has been reported previously in a patient with DCM, and was not reported in 320 control alleles (Olson T et al., 2011). Functional studies show that E54K decreases calcium sensitivity, reduces actin binding, and results in decreased contractility leading to cardiomyopathy pehnotype (Mirza M et al., 2005; Borovikov Y et al., 2009; Memo M et al., 2013). The E54K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the E54K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is completely conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, pathogenic variants in nearby residues (D58H, E62Q, A63V) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In summary, E54K in the TPM1 gene is interpreted as a pathogenic variant. -

Oct 18, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1Y Pathogenic:1 Other:1

Apr 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 15, 2012

Leiden Muscular Dystrophy (TPM1)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Hypertrophic cardiomyopathy Uncertain:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 54 of the TPM1 protein (p.Glu54Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 11273725). ClinVar contains an entry for this variant (Variation ID: 12458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 16043485, 17556658, 19222994, 19646950, 23077624, 23539503, 25520664, 27878731). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
CardioboostCm	Uncertain	0.66
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;D;.;D;D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.6	L;L;.;.;L;.;L;.
PROVEAN	Uncertain	-2.5	N;N;.;D;N;N;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;.
Sift4G	Benign	0.22	T;T;D;D;T;T;T;.
Polyphen		0.92, 0.95	.;.;.;.;P;P;.;.
Vest4		0.86
MutPred		0.68		.;.;.;.;.;Gain of MoRF binding (P = 0.0166);.;.;
MVP		0.97
MPC		2.4
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.98

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: rs104894505; hg19: chr15-63336271; COSMIC: COSV51259749; COSMIC: COSV51259749;