rs199476321

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_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 (★★).

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:12O:1

Conservation

PhyloP100: 8.02

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 Pathogenic. Variant got 17 ACMG points.

PM1

In a coiled_coil_region (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, 0.963

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. Variant chr15-63064133-T-C is described in Lovd as [Pathogenic]. Variant chr15-63064133-T-C is described in Lovd as [Likely_pathogenic].

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

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250772

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135550

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	TPM1: PM2, PM5, PP3, PS3:Supporting, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2023	PP2, PP3, PS3, PS4_moderate -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 04, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	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. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 13, 2021

- -

Dilated cardiomyopathy 1Y

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

KTest Genetics, KTest

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 07, 2016

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The p.M281T pathogenic mutation (also known as c.842T>C), located in coding exon 9 of the TPM1 gene, results from a T to C substitution at nucleotide position 842. The methionine at codon 281 is replaced by threonine, an amino acid with some similar properties. 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 SL, Circulation 2003 Jul; 108(4):445-51; Olivotto I, Mayo Clin. Proc. 2008 Jun; 83(6):630-8; Coppini R, J. Am. Coll. Cardiol. 2014 Dec; 64(24):2589-600; Otsuka H, Circ. J. 2012; 76(2):453-61; Walsh R et al. Genet. Med., 2017 02;19:192-203; Tran Vu MT et al. Circ. J., 2019 Aug;83:1908-1916). 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 LM et al. Int J Cardiol, 2020 Sep). In addition, studies suggest this alteration has an impact on protein function, but the clinical relevance of these findings is uncertain (Gupte TM, J. Biol. Chem. 2015 Mar; 290(11):7003-15; Dorsch LM et al. Int J Cardiol, 2020 Sep). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

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;.;.;.

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

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