chr1-201364336-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001276345.2(TNNT2):c.451C>T(p.Arg151Trp) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R151Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 5.39

Variant links:

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 links:

ENSG00000286600 (HGNC:):

ENSG00000286600 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201364335-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3337677.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 1-201364336-G-A is Pathogenic according to our data. Variant chr1-201364336-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201364336-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.451C>T	p.Arg151Trp	missense_variant	Exon 11 of 17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 link	c.451C>T	p.Arg151Trp	missense_variant	Exon 11 of 17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726660

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1D

Pathogenic:5

Jan 01, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.451C>T (p.Arg151Trp) in TNNT2 gene has been reported in individuals and families affected with dilated cardiomyopathy (Li D et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic .The p.Arg151Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 151 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg151Trp in TNNT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 23, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Some variants have been reported to cause both DCM and HCM, even within the same family (PMID: 26507537). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated troponin domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with TNNT2-related cardiomyopathies including many with DCM, and is often annotated as p.(R141W) using an alternative transcript. It has been reported as de novo in some individuals, and has also been observed to segregate with the disease in families (ClinVar, PMID: 26656454). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Affects cardiac muscle contractile dynamics by decreasing Ca2+ sensitivity of activation, reducing affinity of Ca2+ binding in the troponin complex, and/or increasing the rate of Ca2+ dissociation from the thin filament (Lu et al., 2003; Mirza et al., 2005; Venkatraman et al., 2005; Robinson et al., 2007; Liu et al., 2012; Sommese et al., 2013; Memo et al., 2013; Gollapudi et al., 2015); 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; This variant is associated with the following publications: (PMID: 24367593, 28166811, 24992688, 25611685, 33336002, 34935411, 25681424, 23539503, 17932326, 12923187, 15623536, 11684629, 15923195, 22675533, 21846512, 15769782, 27936050, 27532257, 24503780, 21310275, 26656454, no PMID, 33025817, 34540771, 33906374, 32746448, 32758068, 34076677, 35288587, 14654368, 18606313) -

Dec 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:2

Jun 23, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNNT2 c.421C>T (p.Arg141Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250316 control chromosomes. c.421C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Li_2001, Millart_2011, Alfares_2015, Long_2015, Walsh_2016). These data indicate that the variant is very likely to be associated with disease. In a large multi-generational family study, the variant was detected in at least 14 affected family members, although several unaffected individuals also carried the variant, suggesting incomplete penetrance (e.g. Li_2001). The variant has also been reported as a de-novo mutation in an individual with sporadic disease (e.g. Long_2015). Multiple publications report in-vitro or in-vivo experimental evidence that the variant results in calcium desensitization in cardiac muscle fibers (e.g. Lu_2003, Mirza_2005, Gollapudi_2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypertrophic cardiomyopathy 2

Pathogenic:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3

Pathogenic:2

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the TNNT2 protein (p.Arg141Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM), segregating with the disease in two multigenerational families (PMID: 11684629, 15769782, 21846512, 24992688, 26656454). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12414). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 14654368, 18349139, 18606313, 23539503, 24367593). For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy

Pathogenic:1

May 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg141Trp variant in TNNT2 has been reported in 3 individuals with DCM and segregated with disease in 16 affected relative from 2 families (Li 2001, Villa rd 2005) Additionally, the variant occurred de novo in 1 individual with LVNC (K laassan 2008). This variant has also been identified by our laboratory in 10 ind ividuals with cardiomyopathy, most of whom were diagnosed with DCM at very young ages (<10 years), segregated with disease in 1 affected relative, and occurred de novo in 1 individual. This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg141Trp variant m ay impact protein function (Lu 2003, Venkatraman 2003, Venkatraman 2005, Mirza 2 005, Robinson 2007, Liu 2012, Memo 2013, Sommerse 2013). In summary, this varian t meets our criteria to be classified as pathogenic for DCM in an autosomal domi nant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segreg ation studies, absence from controls, and functional evidence. -

Familial isolated dilated cardiomyopathy

Pathogenic:1

Apr 20, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:1

Aug 04, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Oct 28, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R141W variant (also known as c.421C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 421. The arginine at codon 141 is replaced by tryptophan, an amino acid with dissimilar properties. This variant, which is also known as p.R151W c.451C>T in another isoform, was reported in multiple individuals with features consistent with dilated cardiomyopathy (DCM), including de novo occurrences (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Long PA et al. J Am Heart Assoc, 2015 Dec;4:[ePub ahead of print]; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854; Lesurf R et al. NPJ Genom Med, 2022 Mar;7:18). In multiple assays testing TNNT2 function, this variant showed functionally abnormal results (Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Robinson P et al. Circ Res, 2007 Dec;101:1266-73; Liu B et al. PLoS One, 2012 Jun;7:e38259; Gollapudi SK et al. Am J Physiol Heart Circ Physiol, 2015 Apr;308:H884-93). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

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

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.0

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

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.79

MutPred

0.62

.;.;.;.;Loss of methylation at K156 (P = 0.1239);.;.;.;.;.;.;Loss of methylation at K156 (P = 0.1239);

MVP

0.94

MPC

1.5

ClinPred

0.99

GERP RS

3.3

Varity_R

0.76

gMVP

0.97

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