rs869312881

Positions:

• chr1-201365286-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001276345.2(TNNT2):​c.316G>A​(p.Glu106Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.06

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 1-201365286-C-T is Pathogenic according to our data. Variant chr1-201365286-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224775.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}. Variant chr1-201365286-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.316G>A	p.Glu106Lys	missense_variant	10/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.316G>A	p.Glu106Lys	missense_variant	10/17		NM_001276345.2	ENSP00000499593	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1D Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2023

Reported in a proband with hypertrophic cardiomyopathy (PMID: 27476098); Reported in a proband from a cohort of individuals with sudden cardiac death, but detailed clinical information was not available (PMID: 34076677); Published functional studies demonstrate a damaging effect: transgenic mice over-expressing E96K developed a cardiomyopathy phenotype (PMID: 20083571); Not observed 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: 33025817, 21483645, 27066506, 27476098, 20083571, 16715312, 34076677) -

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

Jan 09, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 96 of the TNNT2 protein (p.Glu96Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy, dilated cardiomyopathy with left ventricular non-compaction and/or sudden cardiac death (PMID: 16715312, 20083571, 34076677; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as p.E108K. ClinVar contains an entry for this variant (Variation ID: 224775). 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%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20083571, 33025817). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;.;D;.;.;.;.;D;.;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;.;.;D;.
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;.;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.6	D;D;.;D;N;.;N;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0060	D;D;.;D;D;.;T;D;D;D;D;D
Sift4G	Benign	0.069	T;T;T;T;T;T;T;T;.;T;D;.
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.;.;.
Vest4		0.68
MutPred		0.62		.;.;.;Gain of MoRF binding (P = 0.0049);.;.;.;.;.;Gain of MoRF binding (P = 0.0049);.;.;
MVP		0.95
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.98

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: rs869312881; hg19: chr1-201334414;