rs367785431

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP3PP5BS2

The NM_001276345.2(TNNT2):c.886C>T(p.Arg296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,610,372 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R296S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:6

Conservation

PhyloP100: 3.54

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:

TNNT2 (HGNC:):

TNNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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, 7 uncertain in NM_001276345.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201359221-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577168.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

PP5

Variant 1-201359221-G-A is Pathogenic according to our data. Variant chr1-201359221-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43676.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=2}. Variant chr1-201359221-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-201359221-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.886C>T	p.Arg296Cys	missense_variant	17/17	ENST00000656932.1	NP_001263274.1	P45379-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.886C>T	p.Arg296Cys	missense_variant	17/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000247

AC:

AN:

242990

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1458206

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

724788

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2023	The p.Arg286Cys variant in TNNT2 has been reported in 16 individuals with HCM (Richard 2003 PMID 12707239, Miliou 2005 PMID 15958377, Mook 2013 PMID 23785128, Coppini 2014 PMID 25524337, Walsh 2016 PMID 27532257, Ingles 2017 PMID 28408708, Burns 2017 PMID 28790153, Luo 2020 PMID 31941943, Parbhudayal 2020 PMID 32290750, LMM unpublished data), and in 1 individual with sudden death (Zhang 2016 PMID 27707468). Two of these individuals had additional variants in different genes associated with cardiomyopathy. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43676), and has been identified in 0.02% (3/18018) of East Asian and 0.003% (3/109994) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). An odds ratio of 17.97 (95% CI 7.03-45.92, p<0.0001) was calculated using probands reported by our laboratory, probands in the literature, and the data from the gnomAD database. This odds ratio would meet PS4_Supporting criteria as recommended by the ClinGen Cardiomyopathy Expert Panel (Kelly 2018 PMID 29300372); however, in light of additional probands with HCM reported by other clinical laboratories in ClinVar, PS4_Moderate was applied. Computational prediction tools and conservation analysis suggest that the p.Arg286Cys variant 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 the p.Arg286Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PM2_Supporting, PP3. -
Likely pathogenic, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This missense variant replaces arginine with cysteine at codon 286 in the tropomyosin binding domain 2 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15958377, 23785128, 25524337, 27532257, 28408708, 28790153, 31941943, 33495596, 33495597). It has also been reported in individuals affected with left ventricular hypertrophy (PMID: 32290750), unknown arrhythmia (PMID: 30847666), and sudden unexplained nocturnal death (PMID: 27707468). This variant has been identified in 6/242990 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	Aug 06, 2024	This missense variant replaces arginine with cysteine at codon 286 in the tropomyosin binding domain 2 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15958377, 23785128, 25524337, 27532257, 28408708, 28790153, 31941943, 33495596, 33495597). It has also been reported in individuals affected with left ventricular hypertrophy (PMID: 32290750), unknown arrhythmia (PMID: 30847666), and sudden unexplained nocturnal death (PMID: 27707468). This variant has been identified in 6/242990 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2024

The p.R286C variant (also known as c.856C>T), located in coding exon 15 of the TNNT2 gene, results from a C to T substitution at nucleotide position 856. The arginine at codon 286 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (also known as p.R293C c.877C>T) has been reported in several individuals with hypertrophic cardiomyopathy (HCM) and was described as co-segregating in a relative with a subclinical form of HCM in one family (Richard P et al. Circulation. 2003;107(17):2227-32; Miliou A et al. Heart. 2005;91(7):966-7; Mook OR et al. J Med Genet. 2013;50(9):614-26; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:Epub ahead of print]; Walsh R et al. Genet Med, 2017 02;19:192-203; Parbhudayal RY et al. J Am Heart Assoc, 2020 04;9:e015316; Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hypertrophic cardiomyopathy 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. 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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (19 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. These alternative changes, p.(Arg293His), p.(Arg293Ser) and p.(Arg293Pro), have been reported as VUS, and have been observed in hypertrophic cardiomyopathy patient cohorts (HCM; LOVD, ClinVar, PMID: 24111713, PMID: 33495597, PMID: 27532257, PMID: 33495596). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported many times as a VUS, but also as likely pathogenic and pathogenic, and has been observed in at least 17 unrelated probands with HCM. Additionally, it was seen once each in an individual with unexplained arrhythmia, sudden unexplained death who also had additional variants in the MYH6 and CACNB2 genes, and another asymptomatic carrier (ClinVar, LOVD, PMID: 27532257, PMID: 33495596, PMID: 33559798, PMID: 28790153, PMID: 31941943, PMID: 28408708, PMID: 25524337, PMID: 27707468, PMID: 12707239, PMID: 23785128, PMID: 15958377, PMID: 30847666). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant appears to segregate within a family with HCM, but it is unclear who was genetically tested (PMID: 15958377). (I) 1007 - No published functional evidence has been identified for this variant. (I) 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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 286 of the TNNT2 protein (p.Arg286Cys). This variant is present in population databases (rs367785431, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15958377, 23785128, 25524337, 32290750). This variant is also known as p.Arg293Cys. ClinVar contains an entry for this variant (Variation ID: 43676). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 26, 2019

- -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Oct 08, 2014

This TNNT2 Arg293Cys variant was first reported by Richard P et al., (2003) as a novel variant in one HCM proband. It has since been identified in other HCM patients (Miliou A., et al 2005; Mook O., et al 2013). Limited segregation analysis by Miliou A., et al (2005) identified 1 family member (son) of the index case to be carrying the Arg293Cys variant. This relative had no echo features of HCM but had ECG criteria for the 'sub clinical form of the disease'. We have identified this variant in 1 HCM proband who also carries a second variant of uncertain significance in MYBPC3 (Gly5Trp). This patient was diagnosed at 62 years and has a maximal wall thickness of 20mm. This variant is present (MAF=0.00001) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational analyses (Polyphen2, CADD, SIFT, Grantham) support a potentially deleterious role. More evidence and additional data is needed to confirm the role of this variant. Thus, we classify this variant as having "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

CardioboostCm

Uncertain

0.57

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

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

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

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

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.79

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

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

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.1

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

REVEL

Uncertain

0.47

Sift

Uncertain

0.0050

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

Sift4G

Pathogenic

0.0

D;D;D;D;D;T;D;T;D;D

Polyphen

1.0

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

Vest4

0.73

MutPred

0.77

.;.;.;.;Gain of catalytic residue at W297 (P = 5e-04);.;.;.;.;.;

MVP

0.97

MPC

1.7

ClinPred

0.95

GERP RS

4.0

Varity_R

0.11

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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