NM_001276345.2:c.304C>G

Variant names:

• chr1-201365298-G-C
• NM_001276345.2:c.304C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_001276345.2(TNNT2):​c.304C>G​(p.Arg102Gly) variant causes a missense change involving the alteration of a non-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. R102L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.02

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]

ENSG00000286600 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr1-201365297-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819
• PP5: Variant 1-201365298-G-C is Pathogenic according to our data. Variant chr1-201365298-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2942386.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.304C>G	p.Arg102Gly	missense_variant	Exon 10 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.304C>G	p.Arg102Gly	missense_variant	Exon 10 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 92 of the TNNT2 protein (p.Arg92Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant disrupts the p.Arg92 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7898523, 8205619, 8951566, 9788962, 10085122, 10449439, 18403758). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;D;.;.;.;.;D;.;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;.;D;.;.;D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.6	D;D;.;.;.;D;.;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;.;.;.;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;.;D;D;.
Polyphen		1.0	.;.;.;D;.;.;.;.;D;.;.;.
Vest4		0.83
MutPred		0.33		.;.;.;Loss of methylation at K103 (P = 0.0446);.;.;.;.;.;Loss of methylation at K103 (P = 0.0446);.;.;
MVP		0.94
MPC		1.6
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.75
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-201334426;