15-63061751-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_001018005.2(TPM1):c.602C>T(p.Thr201Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T201T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 6.10

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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, 0.809

PP5

Variant 15-63061751-C-T is Pathogenic according to our data. Variant chr15-63061751-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181668.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}. Variant chr15-63061751-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.602C>T	p.Thr201Met	missense_variant	Exon 6 of 10	ENST00000403994.9	NP_001018005.1	P09493-1D9YZV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM1	ENST00000403994.9 link	c.602C>T	p.Thr201Met	missense_variant	Exon 6 of 10	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrate p.(T201M) results in reduced calcium transient; however, the correlation with these findings to the clinical phenotype is unclear (PMID: 32882290); This variant is associated with the following publications: (PMID: 35029218, 34681814, 31983221, 32746448, 36264615, 23349452, 32882290) -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy

Pathogenic:2

May 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 201 in the actin binding domain of the TPM1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study using transfected cardiomyocytes has shown that this variant may impact calcium transients (PMID: 32882290). This variant has been reported in multiple unrelated individuals affected with dilated cardiomyopathy (PMID: 23349452, 31983221, 32746448, 32882290). In one large family, this variant has been shown to segregate with disease in 12 affected individuals ranging in age from 21 to 84 years; this variant was also present in 16 unaffected carriers, ranging in age from 3 to 56 years. By the age of 60, 55% of individuals carrying this variant in this family were diagnosed with dilated cardiomyopathy (PMID: 32882290). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 201 of the TPM1 protein (p.Thr201Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 23349452, 31983221, 32882290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181668). 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: 32882290). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1Y

Uncertain:1

Jul 03, 2024

KardioGenetik, Herz- und Diabeteszentrum NRW

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS3, PS4mod -

Cardiovascular phenotype

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T201M variant (also known as c.602C>T), located in coding exon 6 of the TPM1 gene, results from a C to T substitution at nucleotide position 602. The threonine at codon 201 is replaced by methionine, an amino acid with similar properties. This variant has been detected in a large kindred with dilated cardiomyopathy; however, while it was detected in a number of affected individuals, it was also detected in several unaffected family members (Dorsch LM et al. Int J Cardiol, 2021 01;323:251-258). This variant has also been detected in individuals from dilated cardiomyopathy cohorts; however, clinical details were limited (van Spaendonck-Zwarts KY et al. Eur J Heart Fail, 2013 Jun;15:628-36; Mazzarotto F et al. Circulation, 2020 02;141:387-398). In vitro assays from one group indicated this variant may impact calcium transients; however, the physiological relevance of this finding is unclear. And cardiac biopsies from variant carriers demonstrated abnormal sarcomere structure (Dorsch LM et al. Int J Cardiol, 2021 01;323:251-258). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

CardioboostCm

Uncertain

0.27

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;D;.;.;.;.;.;.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.4

M;.;M;M;M;.;.;.;.

PROVEAN

Uncertain

-3.3

D;D;D;D;.;.;D;.;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0080

D;D;D;D;.;.;D;.;D

Sift4G

Uncertain

0.036

D;D;D;D;.;.;D;.;D

Polyphen

0.57

P;P;.;.;P;.;.;.;.

Vest4

0.81

MutPred

0.55

.;Loss of phosphorylation at T243 (P = 0.0891);.;.;.;.;.;.;.;

MVP

0.94

ClinPred

0.97

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over