rs45608937

Variant names:

• chr1-201364306-G-A
• rs45608937
• NM_001276345.2:c.481C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_001276345.2(TNNT2):​c.481C>T​(p.Arg161Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,296 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10
• Conservation: PhyloP100: 1.20
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_001276345.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.481C>T	p.Arg161Cys	missense_variant	Exon 11 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.481C>T	p.Arg161Cys	missense_variant	Exon 11 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248806 AF XY: 0.00000742

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460296 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726474

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111896

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000364 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:2

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 151 of the TNNT2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257) and in two individuals affected with dilated cardiomyopathy (PMID: 19412328, 21483645). This variant has been identified in 1/248806 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy Pathogenic:1

Mar 01, 2024

Lildballe Lab, Aarhus University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PP2(m) PP1(m) PP3(sup) -

not specified Uncertain:1

May 31, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNNT2 c.451C>T (p.Arg151Cys) results in a non-conservative amino acid change located in the Tm binding domain (Hershberger_2009) of 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 250588 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.451C>T has been reported in the literature in individuals affected with dilated cardiomyopathy, hypertrophic cardiomyopathy and left ventricular noncompaction cardiomyopathy, as well as in unaffected individuals in one family (Hershberger_2008, Hershberger_2009, Walsh_2016, Ware_2018, Liu_2019, Mazzarotto_2020, Carnevale_2020). At least one functional study reports this variant results in decreased Ca2+ sensitivity in skinned cardiac muscle fibers (Hershberger_2009). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dilated cardiomyopathy 1D Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS4, PP3, PM2_supporting, PS3_supporting, PS4_moderate -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R151C variant (also known as c.451C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 451. The arginine at codon 151 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported as homozygous in an individual with dilated cardiomyopathy (DCM); however, her homozygous sibling and three heterozygous family members were unaffected (Hershberger RE et al. Clin Transl Sci, 2008 May;1:21-6). This variant has also been detected in DCM and hypertrophic cardiomyopathy genetic testing cohorts as well as a left ventricular noncompaction cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203; Rieger AC et al. EBioMedicine, 2019 Oct;48:377-385; Liu S et al. Int J Cardiol. 2020 Mar;302:117-123; Mazzarotto F et al. Circulation. 2020 Feb;141(5):387-398). One study indicated this variant may impact protein function through altered calcium sensitivity, but the clinical impact of these findings has not been demonstrated (Hershberger RE et al. Circ Cardiovasc Genet, 2009 Aug;2:306-13). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Dec 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 151 of the TNNT2 protein (p.Arg151Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or left ventricular noncompaction (PMID: 20031601, 27532257, 31918855, 31983221; Invitae). ClinVar contains an entry for this variant (Variation ID: 537256). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

TNNT2-related disorder Uncertain:1

Oct 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNNT2 c.451C>T variant is predicted to result in the amino acid substitution p.Arg151Cys. This variant was reported in the homozygous state in an individual with idiopathic dilated cardiomyopathy; however, the variant was also found in the homozygous state in an asymptomatic sibling and both unaffected parents were heterozygous (Hershberger et al 2008. PubMed ID: 19412328; Hershberger RE et al 2009. PubMed ID: 20031601). This variant was also reported in a familial case of dilated cardiomyopathy (Carnevale A et al 2020. PubMed ID: 32969603) and in one case from a large cohort study of patients with dilated cardiomyopathy (Mazzarotto F et al 2020. PubMed ID: 31983221). The c.451C>T was also reported in a patient with left ventricular noncompaction cardiomyopathy; however, the patient carried additional variants in other relevant cardiac genes (Table S1 in Liu S et al 2019. PubMed ID: 31918855). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-201333434-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;D;.;.;.;.;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;.;D;.;.
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.;.;.;.;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.5	D;D;.;D;D;.;.;.;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;.;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		0.64
MutPred		0.44		.;.;.;.;Loss of MoRF binding (P = 0.014);.;.;.;.;.;.;Loss of MoRF binding (P = 0.014);
MVP		0.95
MPC		1.6
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.38
gMVP		0.98
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs45608937; hg19: chr1-201333434; COSMIC: COSV99372078; COSMIC: COSV99372078;