rs45586240

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001276345.2(TNNT2):c.643C>T(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.304

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 38 pathogenic changes around while only 2 benign (95%) 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 chr1-201361988-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

PP5

Variant 1-201361989-G-A is Pathogenic according to our data. Variant chr1-201361989-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180554.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}. Variant chr1-201361989-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	14/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.643C>T	p.Arg215Trp	missense_variant	14/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 16, 2019

- -

Primary familial dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 21, 2019

Variant summary: TNNT2 c.613C>T (p.Arg205Trp) 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 allele was found at a frequency of 4.1e-06 in 246252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.613C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Hershberger 2008, Hershberger 2009, Rampersaud 2011, Walsh 2017, Akinrinade 2015, Ware 2018, van Spaendonck-Zwarts 2013), and in one patient with severe Hypertrophic Cardiomyopathy (HCM), however in this case the patient also carried another causative variant pathogenic for HCM (MYL2 c.173G>A (p.R58Q)) (Jaafar 2015). These data indicate that the variant is likely to be associated with disease. Two functional studies reported the variant to reduce calcium sensitivity (Hershberger 2009, Michael 2016), that is consistent with the cellular pathomechanism observed for other variants associated with DCM (see e.g. in England 2017). In addition, a different variant at the same codon has been reported in association with DCM (p.Arg205Leu), indicating the functional significance of this amino acid. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2022

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: 31983221, 30847666, 15542288, 22337857, 21483645, 23349452, 20031601, 27532257, 25649125, 27576561, 19412328, n/a, 28352236, 23897817) -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Apr 29, 2014

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 205 of the TNNT2 protein (p.Arg205Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 20031601, 23349452, 26084686, 26779504, 27532257, 30847666, 31983221). This variant is also known as c.634C>T (p.R212W). ClinVar contains an entry for this variant (Variation ID: 180554). 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: 20031601, 27411801). This variant disrupts the p.Arg205 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26498512; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2024

The p.R205W variant (also known as c.613C>T), located in coding exon 12 of the TNNT2 gene, results from a C to T substitution at nucleotide position 613. The arginine at codon 205 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited in some cases (Hershberger RE et al. Clin Transl Sci, 2008 May;1:21-6; Hershberger RE et al. Circ Cardiovasc Genet, 2009 Aug;2:306-13; van Spaendonck-Zwarts KY et al. Eur. J. Heart Fail., 2013 Jun;15:628-36; Walsh R et al. Genet Med, 2017 02;19:192-203; Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). Functional studies suggest this alteration has an impact on calcium sensitivity (Hershberger RE et al. Circ Cardiovasc Genet, 2009 Aug;2:306-13). 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

Pathogenic

0.97

CardioboostCm

Uncertain

0.85

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.36

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.86

MutPred

0.74

.;.;.;.;Loss of methylation at K220 (P = 0.0552);.;.;.;.;.;.;

MVP

0.97

MPC

1.4

ClinPred

1.0

GERP RS

1.1

Varity_R

0.81

gMVP

0.81

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