rs727504245

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP5BS2

The NM_001276345.2(TNNT2):c.341C>T(p.Ala114Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000266 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A114E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:10

Conservation

PhyloP100: 3.98

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 1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001276345.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201365261-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403198.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP5

Variant 1-201365261-G-A is Pathogenic according to our data. Variant chr1-201365261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177633.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=8, Likely_pathogenic=1}. Variant chr1-201365261-G-A is described in Lovd as [Pathogenic]. Variant chr1-201365261-G-A is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.341C>T	p.Ala114Val	missense_variant	10/17	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.341C>T	p.Ala114Val	missense_variant	10/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000159

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727242

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000688

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 22, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 26, 2023	This missense variant replaces alanine with valine at codon 104 in the tropomyosin binding domain 1 of the TNNT2 protein. This variant is also known as c.341C>T, p.Ala114Val based on transcript NM_000364.4. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein binds to tropomyosin (TPM1) normally, although it may be less effective than wild type in promoting tropomyosin binding to actin (PMID: 11606294). It has also been shown that the variant does not significantly change maximum isometric force development or Ca2+ sensitivity (PMID: 14722098). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 28408708, 27532257, 28790153, 33297573; DOI:10.13362/j.jpmed.202001002; communication with an external laboratory; ClinVar SCV000541918.9) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537). However, three of these individuals also carried a pathogenic variant in the MYH7 or MYBPC3 gene (PMID: 23396983), suggesting that this TNNT2 variant may not have been the primary cause of disease in these individuals. This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces alanine with valine at codon 104 in the tropomyosin binding domain 1 of the TNNT2 protein. This variant is also known as c.341C>T, p.Ala114Val based on transcript NM_000364.4. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein binds to tropomyosin (TPM1) normally, although it may be less effective than wild type in promoting tropomyosin binding to actin (PMID: 11606294). It has also been shown that the variant does not significantly change maximum isometric force development or Ca2+ sensitivity (PMID: 14722098). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 28408708, 27532257, 28790153, 33297573; DOI:10.13362/j.jpmed.202001002; communication with an external laboratory; ClinVar SCV000541918.9) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537). However, three of these individuals also carried a pathogenic variant in the MYH7 or MYBPC3 gene (PMID: 23396983), suggesting that this TNNT2 variant may not have been the primary cause of disease in these individuals. This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Apr 19, 2017	TNNT2 Ala104Val has been previously reported in a number of HCM cases, however to-date no familial segregation has been noted (LMM, personal communication; Walsh R et al., 2017; Lopes LR, et al., 2013; Pasquale F, et al., 2012; Nakajima-Taniguchi C, et al., 1997). In vitro functional assays suggest that the variant alters tropomyosin binding (Hinkle A & Tobacman LS, 2002) and calcium sensitivity (Harada K & Potter JD, 2004), however this may not necessarily translate to altered protein function in vivo. The variant is present as a singleton event in Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in a HCM proband of Middle Eastern descent. The proband has no family history of disease or sudden cardiac death. Computational tools SIFT, PolyPhen-HCM and PolyPhen-2 predict this variant to have a deleterious effect, however MutationTaster predicts this variant to be a "polymorphism". In summary, based on reports in several HCM probands, as well as rarity in the general population and some evidence of altered protein function in functional assays, we classify TNNT2 Ala104Val as a variant of "uncertain significance" -
Uncertain significance, criteria provided, single submitter	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

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 28, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 104 of the TNNT2 protein (p.Ala104Val). This variant is present in population databases (rs727504245, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9140840, 23396983, 27532257, 28790153, 31737537, 33297573; Invitae). This variant is also known as Ala114Val. ClinVar contains an entry for this variant (Variation ID: 177633). 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: 11606294, 14722098, 33025817). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1D

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP2,PP3. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2022

The p.Ala104Val variant in TNNT2 has been identified in at least 10 individuals with HCM (Nakajima-Taniguchi 1997, Pasquale 2012, Walsh 2017, Marschall 2019, Burns 2017, Invitae pers. comm., LMM data). This variant has been reported in ClinVar (ID 177633) and has been identified in 4/251490 chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Ala104Val variant impacts protein function (Palm 2001, Hinkle 2003, Harada 2004). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala104Val variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS3_Supporting. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2023

The p.A104V variant (also known as c.311C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 311. The alanine at codon 104 is replaced by valine, an amino acid with similar properties. This variant has been detected in an individual with hypertrophic cardiomyopathy (HCM) and family history of HCM and sudden death; however, gene analysis may have been limited (Nakajima-Taniguchi C et al. J. Mol. Cell. Cardiol. 1997 Feb;29(2):839-43). This variant (also referred to as p.A114V) has also been detected in additional HCM cohorts or cohorts referred for HCM genetic testing; however, in several cases, clinical detail or gene analysis was limited or the variant co-occurred with pathogenic mutations in other cardiomyopathy-associated genes. In addition, some reported cases may overlap (Pasquale F et al. Circ Cardiovasc Genet. 2012 Feb;5(1):10-7; Lopes LR et al. J Med Genet. 2013 Apr;50(4):228-39; Ingles J et al. Circ Cardiovasc Genet. 2017 Apr;10(2); Walsh R et al. Genet. Med. 2017 02;19(2):192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10(12); Gorzynski JE et al. N Engl J Med. 2022 Feb;386(7):700-702). In vitro studies indicate this variant may alter some aspects of protein function; however, the physiological relevance of the findings is unclear (Palm T et al. Biophys. J. 2001 Nov;81(5):2827-37; Harada K et al. J. Biol. Chem. 2004 Apr;279(15):14488-95). This amino acid position is poorly 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

Benign

0.18

CardioboostCm

Uncertain

0.14

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

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

Eigen

Benign

0.17

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.58

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

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.2

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

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.1

N;N;.;.;.;.;N;N;N;N;N

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0040

D;D;.;.;.;.;T;D;D;D;D

Sift4G

Benign

0.12

T;T;T;T;T;T;T;T;.;T;D

Polyphen

0.77, 0.77

.;.;.;P;.;.;.;.;P;.;.

Vest4

0.58

MutPred

0.62

.;.;.;Gain of MoRF binding (P = 0.4268);.;.;.;.;.;Gain of MoRF binding (P = 0.4268);.;

MVP

0.96

MPC

0.65

ClinPred

0.66

GERP RS

4.1

Varity_R

0.12

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 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