1-201359221-G-T

Position:

• chr1-201359221-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001276345.2(TNNT2):​c.886C>A​(p.Arg296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.54

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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr1-201359221-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43676.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=2}.
• PP5: Variant 1-201359221-G-T is Pathogenic according to our data. Variant chr1-201359221-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 577168.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.886C>A	p.Arg296Ser	missense_variant	17/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.886C>A	p.Arg296Ser	missense_variant	17/17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg286 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 12860912, 23785128, 26507537). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 577168). 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 arginine, which is basic and polar, with serine, which is neutral and polar, at codon 286 of the TNNT2 protein (p.Arg286Ser). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2018

The p.R286S variant (also known as c.856C>A), located in coding exon 15 of the TNNT2 gene, results from a C to A substitution at nucleotide position 856. The arginine at codon 286 is replaced by serine, an amino acid with dissimilar properties. Three different alterations located at the same position, p.R286C, p.R286H, and p.R286H, have been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al., Circulation 2003 Jul; 108(4):445-51; Andersen PS et al., Hum. Mutat. 2009 Mar; 30(3):363-70; Berge KE et al., Clin. Genet. 2014 Oct; 86(4):355-60; Chiou KR et al., J Cardiol 2015 Mar; 65(3):250-6; Lopes LR et al., Heart 2015 Feb; 101(4):294-301; Ripoll-Vera T et al., Rev Esp Cardiol (Engl Ed) 2016 Feb; 69(2):149-58; Richard P et al. Circulation. 2003;107(17):2227-32; Mook OR et al. J Med Genet. 2013;50(9):614-26; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600). This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Benign	0.058
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;.;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	.;.;.;.;L;.;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	D;D;.;.;.;D;.;.;D;D
REVEL	Benign	0.21
Sift	Benign	0.033	D;D;.;.;.;D;.;.;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D
Polyphen		0.36	.;.;.;.;B;.;.;.;.;.
Vest4		0.57
MutPred		0.67		.;.;.;.;Loss of methylation at R296 (P = 0.0129);.;.;.;.;.;
MVP		0.93
MPC		1.5
ClinPred		0.97	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.59

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: rs367785431; hg19: chr1-201328349;