1-201363348-C-T

Variant names:

• chr1-201363348-C-T
• rs397516471
• NM_001276345.2:c.548G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.548G>A​(p.Arg183Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R183G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.98

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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr1-201363349-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-201363348-C-T is Pathogenic according to our data. Variant chr1-201363348-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201363348-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.548G>A	p.Arg183Gln	missense_variant	Exon 12 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.548G>A	p.Arg183Gln	missense_variant	Exon 12 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Dec 29, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

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. p.Arg173Gln has been previously associated with DCM—and shown to segregate with disease in five affected members of the same family, including one sudden cardiac death. It has also been reported in another, unrelated case of sudden cardiac death. Van Acker et al. (2009) reported this variant to co-segregate with disease in five individuals from three generations of a family affected by DCM. The family’s race is not mentioned, but the researchers were located in Belgium. The proband had prenatal-onset disease (identified by fetal echocardiogram), and her brother also had DCM as a newborn; they and three other clinically affected relatives carried the Arg173Gln variant. This includes the proband’s mother and maternal uncle (the uncle’s affected son was not tested for the variant). It also includes the maternal grandmother, who had died suddenly of “arrhythmia” at the age of 47 and could not be tested, but her husband tested negative for the variant. The proband’s sister, the only unaffected mutation carrier, remained asymptomatic and had normal findings on echocardiography at the age of 21 years. In addition, Hernandez Del Rincon et al. (2011) reported in a poster session that they found this variant in a case of sudden cardiac death in Spain (19th International Association of Forensic Sciences World Meeting). The brief poster abstract does not contain additional phenotype data for the deceased, such as whether DCM was detected, although it mentions that a complete autopsy was performed. Variation at this and nearby loci of TNNT2 has been associated with disease. Arg173Trp (another variant at this same codon) has been seen in at least 3 unrelated individuals with cardiomyopathy and shown to segregate with disease in 4 members of a SCICD family with DCM (please see that variant analysis). Ala172Ser has been reported as a pathogenic mutation causing DCM; Glu163Lys, Glu163Arg, and Ser179Phe have been reported as pathogenic mutations causing HCM (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). This is a chemically semi-conservative amino acid change: The variant substitutes a positively-charged amino acid (Arginine) with a polar, uncharged amino acid (Glutamine). The Arginine at position 173 is highly conserved across vertebrate evolution, although in zebrafish and medaka fish it is instead a positively-charged Lysine and in lamprey a Methionine. In silico analysis (PolyPhen-2) predicts the Arg173Gln variant to be “probably damaging.” Van Acker et al. (2009) did not observe the variant in 100 presumably healthy control individuals. Their race is not mentioned, but the study was conducted in Belgium. The variant was not seen in 3509 Caucasian individuals in NHLBI’s Exome Variant Server, nor in 1869 African American individuals (http://evs.gs.washington.edu/EVS/). The phenotype of these individuals is not publicly available, however the cohort has been screened to exclude those with evidence of Mendelian cardiac disease. The variant is not reported in 1000 Genomes (http://browser.1000genomes.org/index.html) (as of December 29, 2011). This contains 70 individuals of Colombian ancestry as well as over 400 Europeans. The patient’s father’s side of the family is Colombian and her mother’s side of the family includes Northern European Caucasian as well as Native American ancestry. The extensive Caucasian control data is most applicable, therefore, if her mother’s side of the family is the one affected. Assessment: Given the strong segregation data for this variant (albeit in only one family), the likely relevance of the Caucasian control data to that family, and two independent reports of sudden cardiac -

Dec 08, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 43649; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22464770, 25163546, 19324435, 28588840, 28669108, 29367539, 33019804) -

Jun 05, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1D Pathogenic:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

KTest Genetics, KTest

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Primary dilated cardiomyopathy Pathogenic:1

Oct 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg173Gln variant in TNNT2 has been identified 3 individuals with DCM (1 w ith infantile onset and 1 with prenatal onset ) and segregated with disease in 6 affected relatives with varying ages of onset from 2 families (Van Acker 2009, Ferlund 2017, LMM data). It was absent from large population studies. Computatio nal prediction tools and conservation analysis are consistent with pathogenicity . Two additional variants involving this codon (p.Arg173Gly and p.Arg173Trp) hav e been identified in individuals with DCM, and p.Arg173Trp is classified as path ogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP criteria ap plied: PM2, PM5, PP1_Moderate, PP3, PS4_Supporting. -

Cardiovascular phenotype Pathogenic:1

Dec 30, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R173Q pathogenic mutation (also known as c.518G>A), located in coding exon 10 of the TNNT2 gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with dilated cardiomyopathy (DCM), and segregated with disease in at least one family (Van Acker H et al. Int. J. Cardiol., 2010 Oct;144:307-9; Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Chauveau S et al. Clin Case Rep, 2017 Jun;5:923-926; Fernlund E et al. Pediatr Cardiol, 2017 Aug;38:1262-1268). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

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 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 173 of the TNNT2 protein (p.Arg173Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 19324435, 22464770, 28669108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43649). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg173 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24119082). 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	0.35
CardioboostCm	Uncertain	0.58
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.5	.;.;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N;N;.;D;.;.;.;.;N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;.;D;.;.;.;.;D;D;D
Sift4G	Uncertain	0.057	T;T;T;T;D;T;T;T;T;T;.
Polyphen		0.99, 1.0	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.78
MutPred		0.44		.;.;.;.;Gain of ubiquitination at K186 (P = 0.0399);.;.;.;.;.;.;
MVP		0.97
MPC		1.2
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.67

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

Other links and lift over

dbSNP: rs397516471; hg19: chr1-201332476; COSMIC: COSV52663323; COSMIC: COSV52663323;