rs45466197

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001276345.2(TNNT2):c.762G>T(p.Glu254Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:2

Conservation

PhyloP100: 1.71

Publications

28 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: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000205 (299/1461868) while in subpopulation NFE AF = 0.000258 (287/1111994). AF 95% confidence interval is 0.000233. There are 0 homozygotes in GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.762G>T	p.Glu254Asp	missense_variant	Exon 15 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.762G>T	p.Glu254Asp	missense_variant	Exon 15 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152182

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000223

AC:

AN:

251480

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000258

AC:

287

AN:

1111994

Other (OTH)

AF:

0.000132

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

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

AF:

0.0000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu244Asp variant (NM_001001430.1 c.732G>T; also referred to as NM_000364.3 c.753G>T p.Glu251Asp) in TNNT2 has been reported in one individual of unspecified ancestry with HCM (Watkins 1995) and one individual of African American ancestry with DCM who carried another variant of unknown significance in the TPM1 gene (Hershberger 2008, Hershberger 2009, Hershberger 2010, Rampersaud 2011), and has been reported in ClinVar (Variation ID#43667). This variant has been identified in 3 individuals with cardiomyopathy tested by our laboratory, one of whom carries a second likely disease-causing variant and had an early onset of disease, and a second who had an additional TNNT2 variant of uncertain significance and an early onset of disease. This variant has been identified in 0.06% (40/66740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45466197). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In vitro studies have shown that the p.Glu244Asp variant may impact protein function (Watkins 1995, Yanaga 1995, Harada 2004, Matsumoto 2009), but it has not been demonstrated whether this can result in disease. The presence of a variant in HCM and DCM probands raises suspicion about its clinical significance as the two cardiomyopathies are caused by different defects at the cellular level. Given the early onset of disease in all individuals carrying this variant in addition to a second variant, it is possible that it is exacerbating disease severity in these cases. In summary, additional data is need to interpret the pathogenicity of this variant for causing primary disease as well as whether it may play a role in modifying the severity of disease due to other causes. -

Nov 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 7898523, 19412328, 28352236, 23299917, 19293840, 20215591, 19473338, 29121657, 14722098, 20031601, 25637381, 19275886, 10085122, 26774798, 27493864, 21483645, 30565988, 33025817, 10467159, 32429250, 30847666, 37937776, 37652022, 36129056, 10497196) -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:3

May 26, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with aspartic acid at codon 244 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Experimental functional studies have shown that the variant does not cause changes in Ca2+ sensitivity of force development but increases maximal force development (PMID: 10085122, 10467159, 14722098, 19293840). Clinical relevance of this observation is not clear. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 30565988), in three individuals affected with dilated cardiomyopathy (PMID: 19412328, 20031601, 21483645), and in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has been identified in 58/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorders, 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. -

Sep 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with aspartic acid at codon 244 of the TNNT2 protein. 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). Experimental functional studies have shown that the variant does not cause changes in Ca2+ sensitivity of force development but increases maximal force development (PMID: 10085122, 10467159, 14722098, 19293840). Clinical relevance of this observation is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 30565988), in individuals affected with dilated cardiomyopathy (PMID: 19412328, 20031601, 21483645), and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has been identified in 58/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorders, 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. -

Dilated cardiomyopathy 1D

Uncertain:2

Dec 19, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (58 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated troponin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as likely benign, and many times as a VUS, in several individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (ClinVar, LOVD, PMID: 30847666). In some of these individuals, additional variants in cardiac genes were found. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected bovine and porcine fibres have been shown to result in a slight increase in maximum ATPase activity, and significant increase in maximum force. The biological significance of these findings is unclear (PMID: 19275886, PMID: 14722098). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Uncertain:2

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 244 of the TNNT2 protein (p.Glu244Asp). This variant is present in population databases (rs45466197, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 7898523, 19412328, 29121657, 30565988, 37652022). This variant is also known as E251D, E254D. ClinVar contains an entry for this variant (Variation ID: 43667). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 10085122, 10467159, 10497196, 14722098, 19275886, 30565988). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dec 29, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Jun 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TNNT2 c.732G>T (p.Glu244Asp) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00022 in 251480 control chromosomes, predominantly at a frequency of 0.00048 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Cardiomyopathy phenotype (0.00018), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.732G>T has been reported in the literature in one individual affected with Hypertrophic Cardiomyopathy (Watkins 1995) and in another individual with Dilated Cardiomyopathy, who also had another variant of unknown significance in the TPM1 gene (Hershberger 2008, Hershberger 2009, Rampersaud 2011). In none of these cases the variant was seen in family members. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. This variant is also known as E251D, E254D. Several publications reported experimental evidence evaluating an impact on protein function. Some studies showed the variant changed the normal protein function: where mutated protein increased the maximum level of ATPase activity with either increasing (Nakaura 1999) but did not affect Ca2+ sensitivity (Yanaga 1999, Harada 2004, Matsumoto 2009), variant caused abnormal troponin function, i.e. impaired troponin binding to the thin filament (Tobacman 1999) and disturbed the protein conformation (Matsuo 2015). While other studies demonstrated no damaging effect from this variant (examples: Lv_ 2018, Pettinato_ 2020). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 14722098, 20031601, 19412328, 19275886, 27493864, 10467159, 21483645, 10497196, 29121657, 7898523, 10085122, 30565988, 33025817, 36129056, 35629155, 37652022). ClinVar contains an entry for this variant (Variation ID: 43667). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Apr 23, 2015

Blueprint Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Hypertrophic cardiomyopathy 2

Uncertain:1

Dec 19, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 07, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Benign

0.095

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Benign

0.18

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.71

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

MetaSVM

Uncertain

0.63

MutationAssessor

Pathogenic

3.2

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

PhyloP100

1.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

N;N;.;.;.;.;.;.;D;N;N

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.95

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

Vest4

0.80

MutPred

0.67

.;.;.;.;Loss of methylation at K257 (P = 0.1193);.;.;.;.;.;.;

MVP

0.94

MPC

0.71

ClinPred

0.39

GERP RS

1.8

Varity_R

0.50

gMVP

0.93

Mutation Taster

=0/100

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over