rs727503512

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_001276345.2(TNNT2):c.547C>T(p.Arg183Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,894 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.43

Publications

86 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 15 ACMG points.

PM1

In a hotspot region, there are 4 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 chr1-201363349-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165542.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

PP5

Variant 1-201363349-G-A is Pathogenic according to our data. Variant chr1-201363349-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 228409.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.547C>T	p.Arg183Trp	missense_variant	Exon 12 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.547C>T	p.Arg183Trp	missense_variant	Exon 12 of 17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000266003), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 25, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg173Trp (c. 517C>T). At the time of testing this variant was novel (had not been reported in association with cardiomyopathy or as a benign common variant), however it has now been seen in a total of 3 unrelated individuals with cardiomyopathy. An unpublished study conducted in our laboratory demonstrated segregation of the variant in a total of four family members with a DCM diagnosis (Liu et al. 2012 published iPSC studies using this family's DNA). Since testing was completed 3 years ago we contacted the testing lab for an update on this variant and they shared that 1 additional individual (no relation to our proband) tested for DCM was genotype positive for the variant. In addition, Millat et al 2010 reported this variant in a patient with HCM (few clinical details and no segregation data were provided). This is a non conservative amino acid change with a hydrophilic, polar Arginine replaced with a hydrophobic, nonpolar Tryptophan. This variant has not been reported as a benign polymorphism (dbSNP, Google). A variant at the same codon, Arg173Gln, has been seen in at least 3 unrelated families with DCM and/or sudden death (including a SCICD family; please see that variant analysis) and shown to segregate with disease in 5 members of one published family with DCM. Variants in nearby codons (p.Ala172Ser and p.Ser179Phe) have been reported in association with cardiomyopathy (Stefanelli et al 2004 and Ho et al 2000). In silico analysis (PolyPhen) predicts the amino acid change to be damaging to protein structure/function. Arginine is highly conserved at residue 173 across species. This variant was not observed in 335 presumably healthy individuals of mixed ethnicity tested at the testing lab The variant is not listed in dbSNP or 1000 genomes. -

Oct 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM2, PS3, PS4 -

Sep 04, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with cardiomyopathy in the published literature and in patients referred for genetic testing at GeneDx (PMID: 24119082, 24205113, 26265630); Published functional studies in cardiomyocytes exhibited altered Ca2+ handling and impaired myofilament regulation (PMID: 22517884); 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: 32458740, 30624779, 26095046, 26237594, 28315121, 27296521, 20800588, 28246128, 24367593, 27335446, 27237981, 24576884, 25690476, 28573431, 22517884, 27721795, 25548614, 26265630, 23074333, 30871747, 30565988, 31373515, 31514951, 31931689, 33083013, 33025817, 33087929, 35653365, 36396199, 24119082, 24205113) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1D

Pathogenic:2

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:2

Nov 27, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.517C>T (p.Arg173Trp) variant in the TNNT2 gene is located on the exon 11 and is predicted to replace arginine with tryptophan at codon 173 (p.Arg173Trp). The variant has been reported in multiple individuals with dilated cardiomyopathy and segregates with the disease in >20 individuals in 4 families (PMID: 24205113, 22517884, 19324435, 35653365). Alternative variant (p.Arg183Gln) disrupting the same amino acid has been interpreted as pathogenic (ClinVar ID: 43649). Functional experiments suggested this variant negatively impacted the myofilament regulation and calcium handling (PMID: 22517884, 24367593). The variant is reported in ClinVar (ID: 228409). The variant is absent in the general population database (gnomAD). Therefore, the c.517C>T (p.Arg173Trp) variant of TNNT2 has been classified as pathogenic. -

Feb 04, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg173Trp variant in TNNT2 has been reported in 20 families with DCM and segregated with disease in >15 affected relatives (Sun 2012 PMID:22517884, Merlo 2012 PMID:24119082, Campbell 2013 PMID:24205113, Gigli 2019 PMID:31514951, Sousa 2019 PMID:30871747, Ramchand 2020 PMID:31931689, Qiat 2020 PMID: 32458740). It was absent from large population studies. In vitro functional studies also provide some evidence that this variant may impact protein function (Sun 2012 PMID:22517884, Sommese 2013 PMID:24367593, Lv 2018 PMID:30565988, Karakikes 2017 PMID: 28246128). In summary, this variant meets our criteria to be classified as pathogenic for DCM in an autosomal dominant manner based on segregation studies, absence from controls, and functional data. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP3. -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 2

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Apr 30, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R173W pathogenic mutation (also known as c.517C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in one or more individuals with features consistent with dilated cardiomyopathy (DCM) and segregated with disease in at least one family (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Campbell N et al. PLoS ONE, 2013 Oct;8:e78104; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). Other variant(s) at the same codon, p.R173Q (c.518G>A), have been identified in individual(s) with features consistent with DCM (Van Acker H et al. Int. J. Cardiol., 2010 Oct;144:307-9; Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Chauveau S et al. Clin Case Rep, 2017 Jun;5:923-926). This amino acid position is well 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Dec 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 173 of the TNNT2 protein (p.Arg173Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22517884, 24205113). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228409). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 22517884, 24367593). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

CardioboostCm

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.82

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

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.9

.;.;.;.;L;.;.;.;.;.;.

PhyloP100

4.4

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.3

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

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.80

MutPred

0.42

.;.;.;.;Gain of ubiquitination at K186 (P = 0.0415);.;.;.;.;.;.;

MVP

0.99

MPC

1.4

ClinPred

1.0

GERP RS

3.9

Varity_R

0.47

gMVP

0.76

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over