rs397516463

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001276345.2(TNNT2):c.418C>T(p.Arg140Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,612,504 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. R140K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 3.82

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 38 pathogenic changes around while only 2 benign (95%) in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 1-201364369-G-A is Pathogenic according to our data. Variant chr1-201364369-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201364369-G-A is described in Lovd as [Pathogenic]. Variant chr1-201364369-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.418C>T	p.Arg140Cys	missense_variant	11/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.418C>T	p.Arg140Cys	missense_variant	11/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726514

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000329

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2021	PS3, PP1_strong, PS4_moderate, PM2_supporting, PM3_supporting, PP3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 01, 2015	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 variant Arg130Cys (R130C; C>T at the nucleotide level) This variant has been reported in at least 5 unrelated cases of HCM, with segregation data for at least 3 families. Koga et al. (1996) first detected it in 3 different Japanese families. The variant was “present in all affected family members” (a total of 6 people), but specific segregation data is not provided. Toricelli et al. (2003) reported Arg130Cys in an HCM patient from Tuscany with only weak segregation data: The variant was found in the proband and his affected sister. Olivotto et al. (2008) appear to be referring to that same proband. Song et al. (2005) found the variant in one Chinese family with a history of SCD, where it segregated with disease in 4 affected family members—although their degree of relationship is not reported. (Also supposedly mentioned in an abstract by Nakata et al. in 1996.) 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. This includes Lys124Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database), Arg131Trp (in DCM/LVNC; Mogensen et al. 2004), Arg131Gly (in DCM; Willott et al. 2010), Arg134Gly (in DCM; Hershberger et al. 2009; Willott et al. 2010), and Arg139His (Morales et al. 2010). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). The Arginine at codon 130 is completely conserved across 32 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In vitro data from Harada & Potter (2004) shows the variant to alter the contractile properties of skinned cardiac fibers. In total the variant has not been seen in ~5670 published controls and publicly available population datasets. There is no variation at codon 130 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect Arg130Cys in more than 100 Japanese controls. Toricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Song et al. (2005) did not find it in 120 Chinese controls. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2024	Published functional studies demonstrate a damaging effect with this variant altering the contractile properties of cardiac fibers (PMID: 14722098); Not observed at significant frequency in large population cohorts (gnomAD); 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: 23283745, 24474197, 28420666, 23074333, 25524337, 26914223, 27532257, 28973951, 17456375, 15563892, 14636924, 30393638, 18533079, 21310275, 8951566, 30555609, 32690703, 32581830, 33025817, 23494605, 28193612, 34929444, 14722098) -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 09, 2023	This missense variant replaces arginine with cysteine at codon 130 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). In vitro and in vivo functional studies in Drosophila and guinea pigs have shown that this variant impairs the function of the TNNT2 protein by causing increased calcium sensitivity, impaired relaxation and reduced cardiac output (PMID: 32581830, 32690703). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 15563892, 17456375, 23283745, 23494605, 25524337, 30297972, 32481709, 35514357, 36291626). This variant has been reported in the homozygous state in an individual affected with hypertrophic cardiomyopathy and no family history of cardiomyopathy (PMID: 30555609). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with hypertrophic cardiomyopathy 2 (MIM#115195) (PMID: 18612386). (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 (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated troponin domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple individuals and families with hypertrophic cardiomyopathy 2 (MIM#115195) (ClinVar, HGMD, PMIDs: 15563892, 25524337, 28973951). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 130 of the TNNT2 protein (p.Arg130Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 14636924, 15563892, 17456375, 23283745, 23494605, 25524337). This variant is also known as p.Arg140Cys. ClinVar contains an entry for this variant (Variation ID: 43636). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 04, 2022	- -

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

Feb 01, 2019

The p.Arg130Cys variant in TNNT2 (ClinVar variation ID: 43636) has been reported in at least 8 families with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 8 individuals across these families (Fujita 2013, Koga 1996, Olivotto 2008, Song 2005, Torricelli 2003, Zou 2013). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg130Cys variant may impact protein function (Harada 2004, Gangadharan 2017). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that the p.Arg130Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2015

The p.R130C variant (also known as c.388C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 388. The arginine at codon 130 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Torricelli F, Am. J. Cardiol. 2003 Dec; 92(11):1358-62. This variant was seen in a four members of a Chinese family affected with HCM (Song L, Clin. Chim. Acta 2005 Jan; 351(1-2):209-16). This variant was also reported in two adolescent Japanese siblings with HCM but also in their unaffected mother; the siblings also carried a second TNNT2 alteration that was present in their father who was affected with HCM (Fujita E, Heart Vessels 2013 Nov; 28(6):785-94). This variant was also reported to co-occur with a missense alteration in MYBPC3 in a Chinese family (Zou Y, Mol. Biol. Rep. 2013 Jun; 40(6):3969-76). In vitro studies suggest this TNNT2 p.R130C alteration may impact calcium sensitivity (Harada K, J. Biol. Chem. 2004 Apr; 279(15):14488-95). This variant was previously reported in the SNPDatabase as rs397516463. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

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

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.88

MVP

0.97

MPC

1.6

ClinPred

0.99

GERP RS

2.2

Varity_R

0.48

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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