rs1131691898

Positions:

• chr1-201361281-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001276345.2(TNNT2):​c.808G>A​(p.Glu270Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E270D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense, splice_region
• Scores: Splicing: ADA: 0.4679
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.74

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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, 9 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.808G>A	p.Glu270Lys	missense_variant, splice_region_variant	15/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.808G>A	p.Glu270Lys	missense_variant, splice_region_variant	15/17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1D Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2017

The E260K variant of uncertain significance in the TNNT2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E260K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Jun 01, 2023

- -

Hypertrophic cardiomyopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2023

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. An algorithm developed specifically for the TNNT2 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). ClinVar contains an entry for this variant (Variation ID: 430315). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 260 of the TNNT2 protein (p.Glu260Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	3.0	.;.;.;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D;.;.;.;.;.;N;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.010	D;D;.;.;.;.;.;T;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;T;T;T;D;T;T;D;.
Polyphen		0.83	.;.;.;.;P;.;.;.;.;.;.
Vest4		0.77
MutPred		0.55		.;.;.;.;Gain of MoRF binding (P = 0.0093);.;.;.;.;.;.;
MVP		0.96
MPC		0.93
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.90
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.71
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: rs1131691898; hg19: chr1-201330409;