rs369181536

chr1-201361325-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001276345.2(TNNT2):c.764C>T(p.Ala255Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9
• Conservation: PhyloP100: 7.92

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 174 pathogenic changes around while only 18 benign (91%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.764C>T	p.Ala255Val	missense_variant	15/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.764C>T	p.Ala255Val	missense_variant	15/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

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: 0.00000274 AC: 4 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	A variant of uncertain significance has been identified in the TNNT2 gene. The c.734 C>T (A245V) variant has been previously reported in association with DCM (Bick et al., 2012; Pugh et al., 2014; Walsh et al., 2017). This variant was first reported in a 69 year-old individual from the offspring cohort of Framingham Heart Study who had features of DCM, including an increased left ventricular diastolic diameter and left atrial diameter, and decreased fractional shortening (Bick et al., 2012). Pugh et al. (2014) also reported this variant in a 53 year-old Caucasian female with a clinical diagnosis and family history of DCM, and no history of skeletal myopathy. Additionally, Chanvat et al. (2016) identified c.734 C>T in their cohort of patients with cardiomyopathy or arrhythmia, although further clinical details describing this patient's specific phenotype were not provided. Thus far, no segregation data are available for any of these published cases. Nevertheless, the c.734 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The c.734 C>T substitution is located in exon 14, and may be functionally significant at mRNA or protein level. At the mRNA level, c.734 C>T occurs at a nucleotide that is conserved across species, and in silico splice prediction algorithms predict this variant may create a cryptic splice donor site upstream of the natural splice donor site in intron 14 and may impact gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. At the protein level, A245V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, although this amino acid substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, flagged submission	clinical testing	Blueprint Genetics	Jun 21, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 06, 2020	This missense variant replaces alanine with valine at codon 245 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). This variant has also been reported in an individual from a cohort of participants that were not pre-selected for a personal or family history of cardiovascular disorders (PMID: 22958901). This variant has been identified in 1/251480 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 09, 2018

proposed classification - variant undergoing re-assessment, contact laboratory -

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

-

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The p.A245V variant (also known as c.734C>T), located in coding exon 13 of the TNNT2 gene, results from a C to T substitution at nucleotide position 734. The alanine at codon 245 is replaced by valine, an amino acid with similar properties. This alteration was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes, as well as in a DCM genetic testing cohort with limited clinical information provided (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 245 of the TNNT2 protein (p.Ala245Val). This variant is present in population databases (rs369181536, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 177873). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Benign	0.015
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;N;.;.;.;.;.;.;N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.011	D;D;.;.;.;.;.;.;D;D;D
Sift4G	Benign	0.077	T;T;T;T;T;T;T;T;T;T;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;.
Vest4		0.57
MVP		0.96
MPC		0.78
ClinPred		0.90	D
GERP RS		2.8
Varity_R		0.48
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369181536; hg19: chr1-201330453;