rs1553282617

chr1-201365300-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001276345.2(TNNT2):c.302A>T(p.His101Leu) variant causes a missense 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. 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. H101Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.302A>T	p.His101Leu	missense_variant	10/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.302A>T	p.His101Leu	missense_variant	10/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2017

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. A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This variant has not been reported in the literature in individuals with TNNT2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 91 of the TNNT2 protein (p.His91Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostCm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	29
Dann	Benign	0.97
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.4	D;D;.;.;.;.;.;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;D;D;D;D;D
Sift4G	Benign	0.093	T;T;T;T;T;T;T;T;.;T;D;.
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;D;.;.;.
Vest4		0.69
MutPred		0.15		.;.;.;Loss of methylation at K103 (P = 0.0736);.;.;.;.;.;Loss of methylation at K103 (P = 0.0736);.;.;
MVP		0.95
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553282617; hg19: chr1-201334428;