chr1-201365281-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1PM1PM2PP3_ModeratePP5

The NM_001276345.2(TNNT2):c.321G>T(p.Lys107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K107E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 3.37

Publications

9 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 11 ACMG points.

PS1

Transcript NM_001276345.2 (TNNT2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

PP5

Variant 1-201365281-C-A is Pathogenic according to our data. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631. Variant chr1-201365281-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 43631.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2 link	c.321G>T	p.Lys107Asn	missense_variant	Exon 10 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.321G>T	p.Lys107Asn	missense_variant	Exon 10 of 17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251484

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

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:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Aug 09, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Lys97Asn variant in TNNT2 has been previously reported in at least 4 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 4 affected relatives from two families, 3 of whom were tested in a research laboratory (Harada 2004 PMID: 15631686, Coppini 2014 PMID: 25524337, Walsh 2017 PMID: 27532257, LMM data). This variant was also identified in 1 individual with DCM and a family history of HCM (possible end-stage HCM, LMM data). This variant has also been reported in ClinVar (Variation ID 43631) and has been identified in 0.0009% (1/113760) European chromosomes in gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies provide conflicting evidence on whether this variant impacts protein function (Gangadharan 2017 PMID: 28973951, Pettinato 2020 PMID: 33025817). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP1, PM2_Supporting, PP3. -

Apr 22, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1D

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Pathogenic:1

Nov 13, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used to clasify this variant: PS3_MOD, PS4_MOD, PP3_MOD, PM2_SUP -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 2

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 97 of the TNNT2 protein (p.Lys97Asn). This variant is present in population databases (rs397516459, gnomAD 0.0009%). This missense change has been observed in individuals with TNNT2-related conditions (PMID: 21185001, 25524337, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 43631). 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. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 33025817). For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Dec 19, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.60

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

PhyloP100

3.4

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0040

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

Polyphen

1.0

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

Vest4

0.90

MutPred

0.63

.;.;.;Loss of ubiquitination at K107 (P = 0.0051);.;.;.;.;.;Loss of ubiquitination at K107 (P = 0.0051);.;.;

MVP

0.97

MPC

1.6

ClinPred

1.0

GERP RS

5.0

Varity_R

0.84

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over