rs45525839

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1PM5PP3_ModeratePP5BS2

The NM_001276345.2(TNNT2):c.430C>T(p.Arg144Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,824 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. R144Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 0.276

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 Uncertain_significance. Variant got 3 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, 10 uncertain in NM_001276345.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201364357-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 1-201364357-G-A is Pathogenic according to our data. Variant chr1-201364357-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127070.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=3}.

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.430C>T	p.Arg144Trp	missense_variant	11/17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 link	c.430C>T	p.Arg144Trp	missense_variant	11/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249858

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135254

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460622

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2024	Reported in association with cardiomyopathy in unrelated patients in published literature and referred for genetic testing at GeneDx (PMID: 27532257, 34853230, 33297573, 38473809); 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: 30565988, 23861362, 33297573, 34853230, 27532257, 38473809, 37652022, 20031601) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 18, 2022	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 11, 2024	This missense variant replaces arginine with tryptophan at codon 134 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33297573), in one individual affected with left ventricular noncompaction (PMID: 34853230), and in one individual affected with dilated cardiomyopathy (PMID: 38473809). This variant has been identified in 1/249858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg134Gly, is considered to be disease-causing (ClinVar variation ID: 43639), suggesting that arginine at this position is important for TNNT2 protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 12, 2021	This missense variant replaces arginine with tryptophan at codon 134 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/249858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 05, 2022

The c.430C>T (p.Arg144Trp) variant identified in TNNT2 has been reported in the literature in at least two individuals affected with hypertrophic cardiomyopathy [PMID: 27532257, 33297573], and has been deposited in ClinVar as a Variant of Uncertain Significance [ClinVar ID:127070]. The c.430C>T variant is observed in 3 out of 588,858 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) which might include individuals with cardiac abnormalities. The variant is located in exon 10 of this 16-exon gene, and is predicted to replace an evolutionarily conserved arginine aminoacid with tryptophan at position 144 in the Troponin domain of the encoded protein [uniport ID: P45379]. In silico predictions are in favor of damaging effect forp.(Arg144Trp) [REVEL score = 0.796]. An in vitro functional study showed that the induced pluripotent stem cell-differentiated cardiomyocytes (iPSC-CMs) carrying thec.430C>T p.(Arg144Trp) variant had an impaired response to isoproterenol when compared to the control iPSC-CMs [PMID: 30565988]. Based on available evidence, this c.430C>T p.(Arg144Trp) variant identified in TNNT2 is classified as Likely Pathogenic. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 134 of the TNNT2 protein (p.Arg134Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 33297573; Invitae). This variant is also known as R144W. ClinVar contains an entry for this variant (Variation ID: 127070). 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: 30565988). This variant disrupts the p.Arg134 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20031601, 22464770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The p.R134W variant (also known as c.400C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 400. The arginine at codon 134 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in two individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10). The variant (referred to as p.R144W c.430C>T) co-occurred with an MYH7 variant in an individual with findings of left ventricular non-compaction findings (Miyake W et al. Int Heart J, 2021;62:1420-1429). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). 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

0.94

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

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

1.0

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

M_CAP

Pathogenic

0.94

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;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.1

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

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;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

0.81

MutPred

0.43

.;.;.;.;Loss of methylation at R141 (P = 0.3203);.;.;.;.;.;.;Loss of methylation at R141 (P = 0.3203);

MVP

0.97

MPC

1.4

ClinPred

0.99

GERP RS

3.3

Varity_R

0.73

gMVP

0.99

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