chr15-63064133-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001018005.2(TPM1):c.842T>C(p.Met281Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,870 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M281R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 8.02

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
dilated cardiomyopathy 1Y
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TPM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a chain Tropomyosin alpha-1 chain (size 283) in uniprot entity TPM1_HUMAN there are 79 pathogenic changes around while only 3 benign (96%) in NM_001018005.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 15-63064133-T-C is Pathogenic according to our data. Variant chr15-63064133-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM1	NM_001018005.2 link	c.842T>C	p.Met281Thr	missense_variant	Exon 9 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.842T>C	p.Met281Thr	missense_variant	Exon 9 of 10	1	NM_001018005.2	ENSP00000385107.4		P09493-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250772

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111938

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000498

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TPM1: PM2, PM5, PP3, PS3:Supporting, PS4:Supporting -

Jun 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP2, PP3, PS3, PS4_moderate -

Aug 12, 2024

GeneDx

Significance: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; Published functional studies suggest a damaging effect as this variant alters the binding affinity of tropomyosin for actin (PMID: 23700264, 23508784, 25548289); This variant is associated with the following publications: (PMID: 12860912, 20965760, 23508784, 23071391, 18533079, 27532257, 25524337, 21823217, 23700264, 22112859, 21835320, 30297972, 31308319, 32882290, 30240712, 34011823, 30847666, 35626289, 36964972, 37652022, 37466024, 33495597, 37946154, 33495596, 24793961, 36555368, 25548289) -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 15, 2012

Leiden Muscular Dystrophy (TPM1)

Significance:not provided

Review Status:no classification provided

Collection Method:curation

- -

Hypertrophic cardiomyopathy

Pathogenic:3

Oct 04, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Met281Thr variant in TPM1 has been reported in at least 13 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 3 affected relatives from 3 families (Van Driest 2003 PMID: 12860912, Olivotto 2008 PMID: 18533079, Otsuka 2012 PMID: 22112859, Sequeira 2013 PMID: 23508784, Coppini 2014 PMID:255224337, Tran Vu 2019 PMID: 31308319, LMM data). It has also been reported in 1 individual with DCM and in the compound heterozygous state with another TPM1 variant in 1 individual with RCM (Dorsch 2021 PMID: 32882290, Nguyen 2021 PMID: 34011823). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID 31885) and has been identified in 0.0008% (1/113468) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Met281Thr variant may impact protein function (Sequeira 2013 PMID: 23508784, Gupte 2015 PMID: 25548289, Dorsch 2021 PMID: 32882290). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP1, PP3, PS3_Supporting. -

Jan 22, 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 methionine with threonine at codon 281 in the alternate splicing region of the TPM1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. In-vitro functional studies using isolated protein have shown that this variant causes an increased sensitivity to calcium, increased thermal stability, altered myosin interaction with thin filament (PMID: 25548289, 36555368). Additionally, functional studies using patient-derived tissue samples have shown that this variant causes loss of sarcomere striations and loss of intact cardiac muscle fibers as well as increased calcium sensitivity (PMID: 23508784, 32882290). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 18533079, 22112859, 24793961, 25524337, 23508784, 27532257, 30847666, 31308319, 33495596, 33495597) and in one individual affected with restrictive cardiomyopathy (PMID: 32882290). This variant has been identified in 1/250772 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the TPM1 protein (p.Met281Thr). This variant is present in population databases (rs199476321, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12860912, 18533079, 20965760, 21835320, 22112859, 25524337, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 31885). 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 tolerated. Experimental studies have shown that this missense change affects TPM1 function (PMID: 25548289). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:2

Jan 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 13, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:2

Mar 19, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.842T>C (p.M281T) alteration is located in exon 9 (coding exon 9) of the TPM1 gene. This alteration results from a T to C substitution at nucleotide position 842, causing the methionine (M) at amino acid position 281 to be replaced by a threonine (T). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/250772) total alleles studied. The highest observed frequency was 0.001% (1/113468) of European (non-Finnish) alleles. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM), and co-segregation was reported in affected family members in some cases (Van Driest, 2003; Olivotto, 2008; Coppini, 2014; Otsuka, 2012; Walsh, 2017; Tran Vu, 2019). This variant was also reported in a child with restrictive cardiomyopathy, who had an additional TPM1 variant detected in trans; her mother and maternal uncle were asymptomatic carriers for only p.M281T, although the uncle reportedly showed mild left ventricular hypertrophy (Dorsch, 2021). This amino acid position is highly conserved in available vertebrate species. Studies suggest this alteration has an impact on protein function, but the clinical relevance of these findings is uncertain (Gupte, 2015; Dorsch, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Dec 22, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PS3_mod, PM2, PM5_supp, PP1, PP2, PP3, PP5 -

Hypertrophic cardiomyopathy 3

Pathogenic:1

Apr 29, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1Y

Pathogenic:1

KTest Genetics, KTest

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

CardioboostCm

Uncertain

0.74

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.98

.;D;.;.;.;D

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

2.9

M;M;M;.;.;.

PhyloP100

8.0

PROVEAN

Uncertain

-2.6

D;D;.;.;.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.013

D;D;.;.;.;D

Sift4G

Pathogenic

0.0010

D;D;.;.;.;D

Polyphen

0.014, 0.039

.;B;B;.;.;.

Vest4

0.95

MutPred

0.86

Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);.;.;

MVP

1.0

ClinPred

0.63

GERP RS

5.8

Varity_R

0.67

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over