rs201048783

chr1-201364305-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_001276345.2(TNNT2):c.482G>A(p.Arg161His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,442 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.15

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201364306-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT2	NM_001276345.2	c.482G>A	p.Arg161His	missense_variant	11/17	ENST00000656932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT2	ENST00000656932.1	c.482G>A	p.Arg161His	missense_variant	11/17		NM_001276345.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248554 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134660

Gnomad AFR exome AF: 0.0000625

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460130 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726362

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 21, 2016	This TNNT2 variant was found in compound heterozygosity with one another TNNT2 variant in a young patient with severe dilated cardiomyopathy. The patient also harbours a pathogenic variant in TTN gene. The combination of these three variants explains this severe phenotype in a such young patient. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 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

Invitae

Jan 19, 2023

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. 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. This variant disrupts the p.Arg151 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in individuals with TNNT2-related conditions (PMID: 32969603), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 437410). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 20530761). 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 sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 151 of the TNNT2 protein (p.Arg151His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D;D;.;D;D;.;.;.;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.;D;D;.;.;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.
Vest4		0.54
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.46
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201048783; hg19: chr1-201333433;