1-201365261-G-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_001276345.2(TNNT2):c.341C>A(p.Ala114Glu) variant causes a missense change. 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. A114V) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
TNNT2
NM_001276345.2 missense
NM_001276345.2 missense
Scores
2
11
7
Clinical Significance
Conservation
PhyloP100: 3.98
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 7 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 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 chr1-201365261-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177633.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=8, Likely_pathogenic=1}.
PP5
Variant 1-201365261-G-T is Pathogenic according to our data. Variant chr1-201365261-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1403198.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
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 | This variant disrupts the p.Ala104 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9140840, 23396983, 27532257, 28790153). 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. 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: 1403198). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28771489; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 104 of the TNNT2 protein (p.Ala104Glu). - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2022 | The p.A104E variant (also known as c.311C>A), located in coding exon 8 of the TNNT2 gene, results from a C to A substitution at nucleotide position 311. The alanine at codon 104 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was detected in a hypertrophic cardiomyopathy (HCM) case; however, clinical details were limited, and an additional cardiac variant was also reported (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). Another alteration at the same codon, p.A104V (c.311C>T), has been described in HCM cohorts; however, in several cases, clinical detail or gene analysis was limited or the variant co-occurred with pathogenic mutations in other cardiomyopathy-associated genes (Nakajima-Taniguchi C et al. J. Mol. Cell. Cardiol. 1997 Feb;29(2):839-43; Lopes LR et al. Heart, 2015 Feb;101:294-301; Ingles J et al. Circ Cardiovasc Genet. 2017 Apr;10(2); Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is poorly 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;D;.;.;.;.;D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;.;D;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;.;.;N;.;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;.;.;.;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;.;.;.;.;T;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;.;T;T
Polyphen
0.75, 0.88
.;.;.;P;.;.;.;.;P;.;.
Vest4
MutPred
0.63
.;.;.;Loss of MoRF binding (P = 0.4017);.;.;.;.;.;Loss of MoRF binding (P = 0.4017);.;
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.