chr1-201363330-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_001276345.2(TNNT2):c.566C>T(p.Ser189Phe) 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
TNNT2
NM_001276345.2 missense
NM_001276345.2 missense
Scores
14
5
1
Clinical Significance
Conservation
PhyloP100: 9.30
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 Pathogenic. Variant got 13 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, 0.818
PP5
Variant 1-201363330-G-A is Pathogenic according to our data. Variant chr1-201363330-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201363330-G-A is described in Lovd as [Pathogenic]. Variant chr1-201363330-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNNT2 | NM_001276345.2 | c.566C>T | p.Ser189Phe | 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.566C>T | p.Ser189Phe | missense_variant | 12/17 | NM_001276345.2 | ENSP00000499593 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Ser179Phe variant in TNNT2 was identified by our study in one individual with familial hypertrophic cardiomyopathy. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser179Phe variant in TNNT2 has been reported in 6 individuals with familial hypertrophic cardiomyopathy, segregated with disease in 6 affected relatives from a cosanguineous, two-generation family. One individual died suddenly at 17 years of age and was homozygous for the variant and the other 5 individuals were heterozygous for the variant (PMID: 11034944). This variant has been reported pathogenic and likely pathogenic in ClinVar and two individuals with this variant in the heterozygous state and with familial hypertrophic cardiomyopathy were reported in ClinVar (Variation ID: 177634). In summary, although additional studies are required to fully establish its clinical significance, the p.Ser179Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP1_Strong (Richards 2015). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Dilated cardiomyopathy 1D Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
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 | Jul 26, 2010 | The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild HCM and in 1 homozygous individual who died early due to a severe form of HCM (Ho 2000). Thi s variant has also been identified by our laboratory in 1 adult and 1 child with HCM, and was absent from large population studies. The Ser179Phe 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), which strongly supports but does not prove that the Ser1 79Phe variant is pathogenic. In summary, this variant is likely to be pathogenic and causative for HCM, though evidence suggests a milder form when present in t he heterozygous state. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2024 | The p.S179F variant (also known as c.536C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 536. The serine at codon 179 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was first reported in a consanguineous family with a history of hypertrophic cardiomyopathy (HCM) and sudden death. Two heterozygous individuals presented with a mild form of HCM; the variant was present in the homozygous state in an individual with a severe phenotype (Ho CY et al., Circulation 2000 Oct; 102(16):1950-5). This variant has also been detected in individuals from additional HCM cohorts or cohorts submitted for HCM genetic testing (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476). Functional studies suggest this variant may impact protein function through increased calcium sensitivity and force development; however, the physiological relevance of this finding has not been fully elucidated (Messer AE et al., Arch. Biochem. Biophys. 2016; doi: 10.1016/j.abb.2016.03.027; Harada K et al. J Biol Chem. 2004 Apr;279(15):14488-95). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of the available evidence, this alteration is likely to be pathogenic. - |
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 24, 2023 | For these reasons, this variant has been classified as 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: 177634). This missense change has been observed in individuals with clinical findings consistent with hypertrophic cardiomyopathy (HCM) , including a homozygous individual with severe HCM and HCM tested at a diagnostic laboratory (PMID: 11034944, 24033266, 27532257). 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 serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 179 of the TNNT2 protein (p.Ser179Phe). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;D;.;.;.;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D;D;D;D;.;.;D;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;.;M;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;.;.;.;.;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;.;.;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;.
Polyphen
1.0
.;.;.;.;D;.;.;.;.;.;D
Vest4
MutPred
0.37
.;.;.;.;Loss of phosphorylation at S189 (P = 0.0373);.;.;.;.;.;.;
MVP
MPC
1.5
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