rs397516456

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_001276345.2(TNNT2):c.304C>T(p.Arg102Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,788 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 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 3.02

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 14 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

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.871

PP5

Variant 1-201365298-G-A is Pathogenic according to our data. 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. Variant chr1-201365298-G-A 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.304C>T	p.Arg102Trp	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.304C>T	p.Arg102Trp	missense_variant	10/17		NM_001276345.2	ENSP00000499593.1		P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

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 SAS 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:

0.00000411

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

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

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies indicate R92W disrupts tropomyosin binding and increases calcium sensitivity of the cardiac thin filament (Palm et al., 2001, Harada et al., 2004; Revera et al., 2008, Manning et al., 2012a, Manning et al., 2012b); 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: 11606294, 22579624, 21310275, 18029407, 19880069, 26955724, 22334656, 10521296, 12860912, 27590665, 28166811, 27532257, 26507537, 30025578, 28202948, 29563334, 16326803, 31513939, 29572196, 33025817, 14722098, 31006259, 33996946, 30847666, 31737537, 33673806, 11346248, 35626289, 35208637, 9060892, 8951566) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 02, 2014	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. TNNT2 Arg92Trp (R92W; at the nucleotide level) This variant has been reported in at least 16 unrelated cases of HCM with good segregation data in 2 families and weak segregation data in two more. Strong functional data is available both in vitro and in a transgenic mouse model. Koga et al. (1996) found Arg92Trp in two Japanese HCM families. The variant was “present in all affected family members” (a total of 5 people), but specific segregation data for each family is not provided. Moolman et al. (1997) detected this variant in 2 South African families of mixed ancestry with HCM. Segregation data was available for one of these families, with five affected family members carrying the variant. Moolman-Smook et al. (1999) detected it in 4 additional HCM probands of mixed ancestry from South Africa. Varnava et al. (2001) detected it in 2 unrelated cases. Fujino et al. (2001)/Shimizu et al. (2003) identified it in 2 Japanese families. In one family, Arg92Trp segregated with disease in 6 affected family members (5 siblings and one of their children). In the other, two affected siblings carried the variant. Ackerman et al. (2002) detected it in one HCM patient at the Mayo Clinic; it segregated with disease in the patient and her mother. Waldmuller et al. (2002) used this variant in developing a microarray screen for recurring HCM variants. Van Driest et al (2003) detected it in another HCM case at the Mayo Clinic. Van Driest et al. (2004) reported a double-heterozygote carrying Arg92Trp plus a Val256Ile variant in MYBPC3. Konno et al. (2005) detected it in 8 Japanese individuals from HCM families (it is not clear if they are related, or how many have LVH).***note that the cases reported in Van Driest et al (2003, 2004) and Ackerman et al (2002) may overlap. Some authors have suggested that p.Arg92Trp in TNNT2 is associated with a higher risk of sudden death with mild or even absent hypertrophy (Moolman et al 1997, 1999). Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Gln (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). 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. Harada & Potter (2004) showed the Arg92Trp variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu variant had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Tryptophan. The Arginine at co -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2024	Variant summary: TNNT2 c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 253031 control chromosomes (gnomAD). c.274C>T has been reported in the literature in multiple individuals affected with Cardiomyopathy (examples: Revera_200, Liu_2013, Fujita_2013, Kassem_2013). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9060892, 17612745, 23233322, 23494605, 24510615, 23711808). ClinVar contains an entry for this variant (Variation ID: 43627). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 08, 2022	This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using in vitro modeling have shown that this variant may result in impaired tropomyosin binding (PMID: 11606294, 14722098). Additionally, functional studies using mouse models have demonstrated systolic dysfunction and decreased ventricular mass (PMID: 16326803). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9060892, 10521296, 11346248, 11560853, 12084606, 12860912, 20414521, 22321274, 23494605, 28615295, 29572196, 9060892, 11346248 23494605, 29572196). It has been shown that this variant segregates with disease in multiple affected family members across multiple families (PMID: 9060892, 11346248 23494605, 29572196). A different variant occurring at the same codon, p.Arg92Gln, is a well documented pathogenic mutation (Clinvar variation ID: 12409), indicating that arginine at this position is important for TNNT2 protein function. This variant has been identified in 2/282802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 26, 2024	This missense variant replaces arginine with tryptophan at codon 92 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies using in vitro modeling have shown that this variant may result in impaired tropomyosin binding (PMID: 11606294, 14722098). Additionally, functional studies using mouse models have demonstrated systolic dysfunction and decreased ventricular mass (PMID: 16326803). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9060892, 10521296, 11346248, 11560853, 12084606, 12860912, 20414521, 22321274, 23494605, 28615295, 29572196, 9060892, 11346248 23494605, 29572196). It has been shown that this variant segregates with disease in multiple affected family members across multiple families (PMID: 9060892, 11346248 23494605, 29572196). A different variant occurring at the same codon, p.Arg92Gln, is a well documented pathogenic mutation (Clinvar variation ID: 12409), indicating that arginine at this position is important for TNNT2 protein function. This variant has been identified in 2/282802 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2015	The p.Arg92Trp variant in TNNT2 has been reported in the literature and by our l aboratory in >20 individuals with HCM and segregated with disease in >15 affecte d relatives from >5 families (Koga 1996, Ackerman 2002, Moolman 1997, Moolman-Sm ook 1999, Fujino 2001, Varnava 2001, Van Driest 2003, Marsiglia 2010, Yang 2011, Fujita 2013; LMM unpublished data). This variant has been identified in 1/66730 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs397516456). Please note that for diseases with clini cal variability or reduced penetrance, pathogenic variants may be present at a l ow frequency in the general population. In vitro functional studies and mouse mo dels provide evidence that the p.Arg92Trp variant impacts protein function (Palm 2001, Harada 2004, Ertz-berger 2005, Manning 2012). In summary, this variant me ets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregatio n studies and functional evidence. -

Hypertrophic cardiomyopathy 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043627, PS1_S). The variant was co-segregated with Cardiomyopathy, hypertrophic, 2 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 9060892, 8951566, 26507537) (PP1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 14722098, 22334656, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.835, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000007, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012409, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the TNNT2 protein (p.Arg92Trp). This variant is present in population databases (rs397516456, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8951566, 9060892, 26507537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43627). 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: 14722098, 22334656). 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: 7898523, 8205619, 9201030, 10085122, 10617660, 14722098, 18403758). 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. -

Dilated cardiomyopathy 1D

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 05, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.R92W pathogenic mutation (also known as c.274C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 274. The arginine at codon 92 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) and has shown strong segregation with the disease (Moolman JC et al, J. Am. Coll. Cardiol. 1997 Mar; 29(3):549-55; Moolman-Smook JC et al, Am. J. Hum. Genet. 1999 Nov; 65(5):1308-20; Varnava AM et al, Circulation 2001 Sep; 104(12):1380-4; Ackerman MJ et al, J. Am. Coll. Cardiol. 2002 Jun; 39(12):2042-8; Fujino N et al, Clin Cardiol 2001 May; 24(5):397-402; Van Driest SL et al, Circulation 2003 Jul; 108(4):445-51). In addition, in vitro studies suggest this alteration might interfere with tropomycin binding (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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

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

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.6

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

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.84

MutPred

0.47

.;.;.;Gain of catalytic residue at M105 (P = 0.0067);.;.;.;.;.;Gain of catalytic residue at M105 (P = 0.0067);.;.;

MVP

0.99

MPC

1.5

ClinPred

0.99

GERP RS

4.1

Varity_R

0.60

gMVP

0.96

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

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

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