1-201365297-C-T

Position:

chr1-201365297-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_001276345.2(TNNT2):c.305G>A(p.Arg102Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,196 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102L) has been classified as Pathogenic.

Frequency

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

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 4.06

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 Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201365298-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 43627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 1-201365297-C-T is Pathogenic according to our data. Variant chr1-201365297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365297-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.305G>A	p.Arg102Gln	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 linkuse as main transcript	c.305G>A	p.Arg102Gln	missense_variant	10/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant impairs tropomyosin binding, calcium signaling, and the myofibrillar assembly (Yanaga et al., 1999; Javadpour et al., 2003; Liu et al., 2012; Robinson et al., 2018; Cai et al., 2020); 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: 30847666, 26507537, 27036851, 29760186, 29725858, 33336002, 31308319, 28735292, 21131475, 12479243, 11158969, 17932326, 12186860, 10085122, 10617660, 10449439, 12952925, 19087273, 24691700, 22675533, 8205619, 18403758, 9788962, 21310275, 27532257, 30022097, 31006259, 31759053, 33673806, 30975432, 26582918, 33025817, 11857753) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 16, 2012	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. Based on the strong case data, strong segregation data, and mouse models, we consider it very likely disease causing. The variant has been seen in at least 8 unrelated cases of HCM (not including the patient) with good segregation data in one family and extensive functional data available—including in transgenic mouse models. In our own center we have seen this variant in at least three unrelated individuals with familial cardiomyopathy. Thierfelder et al. (1994) identified Arg92Gln in one HCM family; it segregated with disease in all 6 affected members (degree of relationship not reported; LOD score 4.1). Watkins et al. (1995) identified Arg92Gln in 3 unrelated HCM families. (LOD score 8.3.) Torricelli et al. (2003) identified it in an HCM case from Tuscany. Morita et al. (2008) found it had occurred de novo in a patient with HCM. Paternity was confirmed, and the parents were clinically unaffected. Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Trp (we categorize both as very likely disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). Oberst et al. (1998) showed transgenic mice carrying Arg92Gln to have increased cardiac myocyte disarray, increased interstitial collagen synthesis, and diastolic dysfunction. Tardiff et al. (1999) also showed the transgenic mouse hearts to have increased interstitial fibrosis, hypercontractility, and diastolic dysfunction. In vitro functional data from Palm et al. (2001) suggests that a change at codon 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Takahashi-Yanaga et al. (2001) showed the variant to impair the inhibitory effect of Troponin I on the sarcomere. Hinkle & Tobacman (2003) showed the variant to impair folding of the troponin T tail domain. Javadpour et al. (2003) found significant changes in cardiac energetics in transgenic mice carrying the variant. [[Note: Other papers to address the altered properties of myocytes containing this variant include Marian et al. 1997, Morimoto et al. 1998, Sweeney et al. 1998, Rust et al.1999, Yanaga et al. 1999, Szczesna et al. 2000, Chandra et al. 2001, Montgomery et al. 2001, Robinson et al. 2002, Solaro et al. 2002, Maass et al. 2004, and others. These are not reviewed here.]] Jimenez & Tardiff (2011) found Arg92Gln transgenic mice had an increased incidence of heart block and a greater frequency of premature ventricular contractions after isoproterenol injections. They also had abnormal autonomic regulation of heart rate. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Glutamine. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” In total the variant has not been seen in ~7030 published controls and publicly available population datsets. There is no variation at codon 92 listed in the NHLBI -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 2

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Mar 08, 2016	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with HCM. Studies have shown that the variant impacts protein function (PMID:8205619). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 03, 1994	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Dilated cardiomyopathy 1D

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 10, 2018

The p.Arg92Gln variant in TNNT2 has been reported in >15 individuals with HCM, i ncluding one de novo occurrence, and segregated with disease in >15 affected rel atives (Thierfelder 1994, Watkins 1995, Morita 2008, Olivotto 2008, Strijack 200 8, Ripoll-Vera 2016, Walsh, 2017, LMM data). In addition, this was absent from l arge population studies. In vitro functional studies have shown that the Arg92Gl n variant impacts protein function (Marian 1997, Yanaga 1999, Robinson 2002, Liu 2012) and transgenic mice carrying this variant develop HCM (Chandar 2001, Ferr antini 2017). In summary, this variant meets criteria to be classified as pathog enic for HCM in an autosomal dominant manner based on case observations, segrega tion studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PS3, PS4, PP1_Strong, PM2. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.R92Q pathogenic mutation (also known as c.275G>A), located in coding exon 8 of the TNNT2 gene, results from a G to A substitution at nucleotide position 275. The arginine at codon 92 is replaced by glutamine, an amino acid with highly similar properties. This alteration (also described as p.R102Q, c.305G>A) has been reported in association with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC) and has shown strong segregation with disease across several families (Thierfelder L, Cell 1994 Jun; 77(5):701-12; Watkins H, N. Engl. J. Med. 1995 Apr; 332(16):1058-64; Torricelli F, Am. J. Cardiol. 2003 Dec; 92(11):1358-62; Strijack B, J Cardiovasc Magn Reson 2008; 10():58; Lopes LR, Heart 2015 Feb; 101(4):294-301; Tian T, Heart Vessels 2015 Mar; 30(2):258-64; Ripoll-Vera T, Rev Esp Cardiol (EnglEd) 2016 Feb; 69(2):149-58). One study also demonstrated this alteration as a de novo mutation in a subject with HCM (Morita H, N. Engl. J. Med. 2008 May; 358(18):1899-908). Several studies have also shown that this alteration has an impact on protein function (Yanaga F, J. Biol. Chem. 1999 Mar; 274(13):8806-12; Palm T, Biophys. J. 2001 Nov; 81(5):2827-37; Robinson P, Circ. Res. 2007 Dec; 101(12):1266-73; Liu B, PLoS ONE 2012; 7(6):e38259). In addition, transgenic mouse models have shown this alteration causes hypercontractility and diastolic dysfunction (Tardiff JC, J. Clin. Invest. 1999 Aug; 104(4):469-81; Oberst L, J. Clin. Invest. 1998 Oct; 102(8):1498-505; Chandra M, Am. J. Physiol. Heart Circ. Physiol. 2001 Feb; 280(2):H705-13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Nov 15, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the TNNT2 protein (p.Arg92Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, left ventricular non-compaction, atypical pattern of myocardial scarring and/or inducible malignant ventricular tachyarrhythmia (PMID: 7898523, 8205619, 8951566, 18403758, 19087273, 19487599, 23233322, 24691700, 25524337). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12409). 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 have shown that this missense change affects TNNT2 function (PMID: 9788962, 10085122, 10449439, 11158969, 12186860). This variant disrupts the p.Arg92 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9060892, 16326803, 22144547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.80

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

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

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

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

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

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

Sift4G

Benign

0.12

T;T;T;T;T;T;T;T;.;T;T;.

Polyphen

1.0

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

Vest4

0.73

MutPred

0.44

.;.;.;Loss of methylation at K103 (P = 0.1214);.;.;.;.;.;Loss of methylation at K103 (P = 0.1214);.;.;

MVP

0.96

MPC

1.5

ClinPred

1.0

GERP RS

5.0

Varity_R

0.52

gMVP

0.95

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