rs483352832

Positions:

chr1-201364327-G-A

Variant summary

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

The NM_001276345.2(TNNT2):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,150 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. R154Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 0.754

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001276345.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201364326-C-G is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.903

PP5

Variant 1-201364327-G-A is Pathogenic according to our data. Variant chr1-201364327-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132943.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=4, Uncertain_significance=3}. Variant chr1-201364327-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-201364327-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	11/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.460C>T	p.Arg154Trp	missense_variant	11/17		NM_001276345.2	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

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:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

249866

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460814

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726726

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with tryptophan at codon 144 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 34213952; ClinVar SCV002025668.1). It has been shown that this variant segregates with disease in 4 affected individuals in one family (PMID: 24992688). This variant has also been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33297573) and in two individuals affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771, 34853230). This variant has been identified in 8/249866 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This missense variant replaces arginine with tryptophan at codon 144 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 34213952; ClinVar SCV002025668.1). It has been shown that this variant segregates with disease in 4 affected individuals in one family (PMID: 24992688). This variant has also been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33297573) and in two individuals affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771, 34853230). This variant has been identified in 8/249866 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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 28, 2020

The heterozygous p.Arg144Trp missense variant identified in TNNT2 has been reported in a South Indian family affected with late-onset familial dilated cardiomyopathy and sudden cardiac death (SCD) [PMID: 24992688]. The variant was detected in four affected family members (one additional obligate carrierdeceasedpatientwhose DNA was not available for analysis) and was absent in eleven unaffected family members [PMID: 24992688]. ClinVar has an entry of this variant [ClinVar ID:132943]. The p.Arg144Trp variant has overall 0.00003 allele frequency in gnomAD database (8 out of 249,866 heterozygous alleles) and 0.00013 allele frequency (4 out of 30,504 heterozygous alleles) in South Asian subpopulation represented in the gnomAD database. The variant affects a moderately conserved residue, is located within functionally important tropomyosin-binding domain (residues ~80-180) and is predicted “deleterious” by multiple in silico prediction tools. In vitro functional experiments suggest that the p.Arg144Trp variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity [PMID: 28973951]. Based on the available evidence, the p.Arg144Trp variant in the TNNT2 gene is assessed as likely pathogenic. -

Dilated cardiomyopathy 1DD

Pathogenic:1

Pathogenic, no assertion criteria provided

not provided

Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology

- -

Primary dilated cardiomyopathy;C0027059:Myocarditis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

- -

Left ventricular noncompaction cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

- -

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

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 144 of the TNNT2 protein (p.Arg144Trp). This variant is present in population databases (rs483352832, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 24992688, 36264615). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg154Trp. ClinVar contains an entry for this variant (Variation ID: 132943). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 28973951, 33025817). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg144Trp variant in TNNT2 has been reported in 1 individual with dilated cardiomyopathy and segregated with disease in 4 affected relatives, including 1 obligate carrier (Rani 2014). It has also been identified in 4/30504 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #132943). An in vitro functional study suggests that this variant may disrupt troponin binding (Gangadharan 2017) and computational prediction tools suggest that it may impact the protein, though this information is not predictive enough to determine pathogenicity.In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PS3_Supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.67

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.90

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

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.2

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

REVEL

Pathogenic

0.78

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;.;D

Polyphen

1.0

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

Vest4

0.68

MVP

0.96

MPC

1.5

ClinPred

0.98

GERP RS

3.3

Varity_R

0.21

gMVP

0.96

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