1-201364366-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001276345.2(TNNT2):​c.421C>G​(p.Arg141Gly) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

TNNT2
NM_001276345.2 missense

Scores

13
6
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 1.06
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 3 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 chr1-201364365-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
Variant 1-201364366-G-C is Pathogenic according to our data. Variant chr1-201364366-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 389145.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNT2NM_001276345.2 linkc.421C>G p.Arg141Gly missense_variant Exon 11 of 17 ENST00000656932.1 NP_001263274.1 P45379-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNT2ENST00000656932.1 linkc.421C>G p.Arg141Gly missense_variant Exon 11 of 17 NM_001276345.2 ENSP00000499593.1 P45379-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Sep 07, 2016
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The novel R131G likely pathogenic variant in the TNNT2 gene has not been published as a pathogenic or benign variant to our knowledge. This 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 R131G 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. This substitution also occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (R131W) has been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), supporting the functional importance of this residue of the protein. Therefore, this variant is likely pathogenic. -

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:1
Oct 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 131 of the TNNT2 protein (p.Arg131Gly). 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. ClinVar contains an entry for this variant (Variation ID: 389145). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNNT2 protein function. This variant disrupts the p.Arg131 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29367541; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
.;.;.;.;D;.;.;.;.;.;D;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D;D;D;.;.;D;.;.
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
.;.;.;.;M;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-6.3
D;D;D;.;.;.;.;.;D;D;D;D
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D;D;D;.;.;.;.;.;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D;D;D;D;D;.;D
Polyphen
1.0, 0.99
.;.;.;.;D;.;.;.;.;.;D;.
Vest4
0.78
MutPred
0.43
.;.;.;.;Loss of stability (P = 0.0826);.;.;.;.;.;.;Loss of stability (P = 0.0826);
MVP
0.96
MPC
1.2
ClinPred
0.96
D
GERP RS
3.2
Varity_R
0.89
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs74315380; hg19: chr1-201333494; API