1-201365630-C-T

Position:

• chr1-201365630-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001276345.2(TNNT2):​c.274G>A​(p.Gly92Arg) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G92E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.82

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-201365629-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3338341.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 1-201365630-C-T is Pathogenic according to our data. Variant chr1-201365630-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365630-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.274G>A	p.Gly92Arg	missense_variant	9/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.274G>A	p.Gly92Arg	missense_variant	9/17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2013

p.Gly82Arg (GGA>AGA): c.244 G>A in exon 8 of the TNNT2 gene (NM_001001430.1). The Gly82Arg mutation in the TNNT2 gene has been reported in one patient with HCM and left ventricular apical aneurysm (Maron M et al., 2008). Gly82Arg results in a non-conservative amino acid substitution of a non-polar Glycine with a positively charged Arginine at a position that is conserved across species. In silico analysis predicts Gly82Arg is probably damaging to the protein structure and function. Mutations in nearby residues (Ile79Asn, Pro80Ser, Glu83Lys, Glu83Asp, Val85Leu) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Gly82Arg mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Hereditary hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disease characterized by myocardial hypertrophy in the absence of other cardiac or systemic causes. HCM is most frequently caused by mutations in genes coding for sarcomeric proteins in the cardiac muscle leading to myocyte disarray, a hallmark feature of HCM. Less commonly, ventricular hypertrophy is a presenting feature of genetic systemic disorders, such as Danon disease, Fabry disease, or mitochondrial cardiomyopathy. HCM has a variable clinical presentation; including palpitations, chest pain, heart failure, syncope, or sudden death, although some individuals may be asymptomatic (Marian A et al., 1995; Maron B, 2002). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). In summary, Gly82Arg in the TNNT2 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -

Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2016

The p.Gly82Arg variant in TNNT2 has been reported in 2 individuals with HCM, seg regated with disease in 4 individuals (including 2 obligate carriers)(Maron 2008 , Judge 2009), and was absent from large population studies. This variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly82Arg variant is likely path ogenic. -

Hypertrophic cardiomyopathy 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;D;.;.;.;.;.;D;.;.;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;.;D;.;.;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	.;.;.;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.4	D;D;.;.;.;.;.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;D;D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D;T;T;D;T;D;D;.;T;D;.
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.;.;.
Vest4		0.71
MutPred		0.15		.;.;.;.;Loss of glycosylation at K88 (P = 0.1233);.;.;.;.;.;.;Loss of glycosylation at K88 (P = 0.1233);.;.;
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.24
gMVP		0.93

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: rs727504255; hg19: chr1-201334758;