chr1-201363349-G-A

Position:

• chr1-201363349-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.547C>T​(p.Arg183Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,894 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. R183Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201363348-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 1-201363349-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.547C>T	p.Arg183Trp	missense_variant	12/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.547C>T	p.Arg183Trp	missense_variant	12/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 25, 2011	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.Arg173Trp (c. 517C>T). At the time of testing this variant was novel (had not been reported in association with cardiomyopathy or as a benign common variant), however it has now been seen in a total of 3 unrelated individuals with cardiomyopathy. An unpublished study conducted in our laboratory demonstrated segregation of the variant in a total of four family members with a DCM diagnosis (Liu et al. 2012 published iPSC studies using this family's DNA). Since testing was completed 3 years ago we contacted the testing lab for an update on this variant and they shared that 1 additional individual (no relation to our proband) tested for DCM was genotype positive for the variant. In addition, Millat et al 2010 reported this variant in a patient with HCM (few clinical details and no segregation data were provided). This is a non conservative amino acid change with a hydrophilic, polar Arginine replaced with a hydrophobic, nonpolar Tryptophan. This variant has not been reported as a benign polymorphism (dbSNP, Google). A variant at the same codon, Arg173Gln, has been seen in at least 3 unrelated families with DCM and/or sudden death (including a SCICD family; please see that variant analysis) and shown to segregate with disease in 5 members of one published family with DCM. Variants in nearby codons (p.Ala172Ser and p.Ser179Phe) have been reported in association with cardiomyopathy (Stefanelli et al 2004 and Ho et al 2000). In silico analysis (PolyPhen) predicts the amino acid change to be damaging to protein structure/function. Arginine is highly conserved at residue 173 across species. This variant was not observed in 335 presumably healthy individuals of mixed ethnicity tested at the testing lab The variant is not listed in dbSNP or 1000 genomes. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	Identified in patients with cardiomyopathy in the published literature and in patients referred for genetic testing at GeneDx (PMID: 24119082, 24205113, 26265630); Published functional studies in cardiomyocytes exhibited altered Ca2+ handling and impaired myofilament regulation (PMID: 22517884); 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: 32458740, 30624779, 26095046, 26237594, 28315121, 27296521, 20800588, 28246128, 24367593, 27335446, 27237981, 24576884, 25690476, 28573431, 22517884, 27721795, 25548614, 26265630, 23074333, 30871747, 30565988, 31373515, 31514951, 31931689, 33083013, 33025817, 33087929, 35653365, 36396199, 24119082, 24205113) -

Dilated cardiomyopathy 1D Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Primary dilated cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 04, 2022	The p.Arg173Trp variant in TNNT2 has been reported in 20 families with DCM and segregated with disease in >15 affected relatives (Sun 2012 PMID:22517884, Merlo 2012 PMID:24119082, Campbell 2013 PMID:24205113, Gigli 2019 PMID:31514951, Sousa 2019 PMID:30871747, Ramchand 2020 PMID:31931689, Qiat 2020 PMID: 32458740). It was absent from large population studies. In vitro functional studies also provide some evidence that this variant may impact protein function (Sun 2012 PMID:22517884, Sommese 2013 PMID:24367593, Lv 2018 PMID:30565988, Karakikes 2017 PMID: 28246128). In summary, this variant meets our criteria to be classified as pathogenic for DCM in an autosomal dominant manner based on segregation studies, absence from controls, and functional data. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 27, 2023	The c.517C>T (p.Arg173Trp) variant in the TNNT2 gene is located on the exon 11 and is predicted to replace arginine with tryptophan at codon 173 (p.Arg173Trp). The variant has been reported in multiple individuals with dilated cardiomyopathy and segregates with the disease in >20 individuals in 4 families (PMID: 24205113, 22517884, 19324435, 35653365). Alternative variant (p.Arg183Gln) disrupting the same amino acid has been interpreted as pathogenic (ClinVar ID: 43649). Functional experiments suggested this variant negatively impacted the myofilament regulation and calcium handling (PMID: 22517884, 24367593). The variant is reported in ClinVar (ID: 228409). The variant is absent in the general population database (gnomAD). Therefore, the c.517C>T (p.Arg173Trp) variant of TNNT2 has been classified as pathogenic. -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2020

The p.R173W pathogenic mutation (also known as c.517C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been detected in several individuals with dilated cardiomyopathy (DCM) and has demonstrated strong segregation with DCM in multiple affected families (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Campbell N et al. PLoS ONE, 2013 Oct;8:e78104; Sousa A et al. Rev Port Cardiol, 2019 02;38:129-139). Studies using induced pluripotent stem cell cardiomyocytes from affected individuals have demonstrated functional impacts (Sun N et al. Sci Transl Med, 2012 Apr;4:130ra47; Sommese RF et al. PLoS ONE, 2013 Dec;8:e83403; Wu H et al. Cell Stem Cell, 2015 Jul;17:89-100; Dai Y et al. Sci Rep, 2020 Jan;10:209). Furthermore, an alternate amino acid substitution at this position, p.R173Q, has also been reported in multiple probands with DCM and has been shown to segregate with disease (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). 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

Oct 14, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the TNNT2 protein (p.Arg173Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22517884, 24205113). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228409). 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. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 22517884, 24367593). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.3	D;D;.;D;.;.;.;.;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;.;D;.;.;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.80
MutPred		0.42		.;.;.;.;Gain of ubiquitination at K186 (P = 0.0415);.;.;.;.;.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.47
gMVP		0.76

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: rs727503512; hg19: chr1-201332477;