chr1-201363394-G-C

Position:

• chr1-201363394-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001276345.2(TNNT2):​c.502C>G​(p.Arg168Gly) 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 Conflicting classifications of pathogenicity (no stars).

• 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: 1.78

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 region_of_interest Disordered (size 99) in uniprot entity TNNT2_HUMAN there are 38 pathogenic changes around while only 2 benign (95%) in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 1-201363394-G-C is Pathogenic according to our data. Variant chr1-201363394-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181620.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.502C>G	p.Arg168Gly	missense_variant	12/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.502C>G	p.Arg168Gly	missense_variant	12/17		NM_001276345.2	ENSP00000499593	A2

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

Mar 23, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 181620). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy (PMID: 23283745, 31514951; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 158 of the TNNT2 protein (p.Arg158Gly). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2016

The R158G variant has been reported previously in one Chinese proband with HCM; additional clinical information and segregation data was not provided (Zou et al., 2013). The R158G variant 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. The R158G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, additional evidence is needed to determine whether this variant is pathogenic or benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;.;.;D;.;.;.;.;.;D;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.018
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	.;D;D;D;D;D;D;.;.;D;.;.
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.6	.;.;.;.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	D;D;.;.;.;.;.;.;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0, 1.0	.;.;.;.;D;.;.;.;.;.;D;.
Vest4		0.80
MutPred		0.42		.;.;.;.;Loss of MoRF binding (P = 0.0292);.;.;.;.;.;.;Loss of MoRF binding (P = 0.0292);
MVP		0.92
MPC		1.6
ClinPred		1.0	D
GERP RS		-2.1
Varity_R		0.73
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs730881103; hg19: chr1-201332522;