1-201364357-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001276345.2(TNNT2):c.430C>G(p.Arg144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R144P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.276

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1D
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy 3
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
cardiomyopathy, familial restrictive, 3
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiomyopathy
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TNNT2 links:

ENSG00000286600 (HGNC:):

ENSG00000286600 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 hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 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 chr1-201364356-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 982844.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

PP5

Variant 1-201364357-G-C is Pathogenic according to our data. Variant chr1-201364357-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43639.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
TNNT2	NM_001276345.2 link	c.430C>G	p.Arg144Gly	missense_variant	Exon 11 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 link	c.430C>G	p.Arg144Gly	missense_variant	Exon 11 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1D

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:1

Feb 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg134Gly variant in TNNT2 has been reported in 1 individual with DCM, was a bsent from 506 control chromosomes, and segregated with disease in 4 affected re latives from 1 family (Hershberger 2008, Hershberger 2009). Data from large popu lation studies is insufficient to assess the frequency of this variant. This var iant has also been identified by our laboratory in 1 Caucasian individual with D CM (this family) and segregated with disease in 3 affected relatives, but was no t detected in 1 other affected relative (more distantly related). Arginine (Arg) at position 134 is conserved in evolution and the change to glycine (Gly) was p redicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely pathogenic, though a dditional studies are required to fully establish its clinical significance. -

Hypertrophic cardiomyopathy 2

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Apr 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20031601, 34161147). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 43639). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 20031601, 33025817). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 134 of the TNNT2 protein (p.Arg134Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

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

PhyloP100

0.28

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.2

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

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.89

MutPred

0.43

.;.;.;.;Gain of methylation at R141 (P = 0.269);.;.;.;.;.;.;Gain of methylation at R141 (P = 0.269);

MVP

0.95

MPC

1.5

ClinPred

1.0

GERP RS

3.3

Varity_R

0.86

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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