rs45520032
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PP3_ModerateBP6BS2
The NM_001276345.2(TNNT2):āc.692T>Cā(p.Ile231Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I231V) has been classified as Uncertain significance.
Frequency
Genomes: š 0.00014 ( 0 hom., cov: 33)
Exomes š: 0.00016 ( 0 hom. )
Consequence
TNNT2
NM_001276345.2 missense
NM_001276345.2 missense
Scores
5
11
4
Clinical Significance
Conservation
PhyloP100: 7.39
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_benign. Variant got -1 ACMG points.
PM1
In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 177 pathogenic changes around while only 18 benign (91%) in NM_001276345.2
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865
BP6
Variant 1-201361940-A-G is Benign according to our data. Variant chr1-201361940-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181604.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=10, Benign=1}. Variant chr1-201361940-A-G is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 22 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TNNT2 | NM_001276345.2 | c.692T>C | p.Ile231Thr | missense_variant | 14/17 | ENST00000656932.1 | NP_001263274.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TNNT2 | ENST00000656932.1 | c.692T>C | p.Ile231Thr | missense_variant | 14/17 | NM_001276345.2 | ENSP00000499593.1 |
Frequencies
GnomAD3 genomes 0.000145 AC: 22AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000143 AC: 36AN: 251490Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135918
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GnomAD4 exome AF: 0.000155 AC: 227AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 104AN XY: 727246
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GnomAD4 genome 0.000144 AC: 22AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74462
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2023 | Variant summary: TNNT2 c.662T>C (p.Ile221Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251490 control chromosomes, predominantly within the Latino- and North-western European subpopulations, at a frequency of 0.00029 and 0.00031 (respectively) in the gnomAD database. The observed variant frequency within these subpopulations is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing cardiomyopathy (0.00018), suggesting that the variant is a benign polymorphism. c.662T>C has been reported in the literature, primarily in settings of multigene panel testing, in individuals affected with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and in a case of sudden arrhythmic death (e.g. Marsiglia_2013, Ripoll-Vera_2016, Campuzano_2017, Ho_2018, Te Rijdt_2019, Verdonschot_2020); however in several of these cases, the variant has been reported as a VUS and/or other variants in cardiac-related genes have also been reported in the same individual. Therefore, these reports do not provide strong evidence to support the variant's association with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant did not differ from wild-type TNNT2 (e.g. Pettinato_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 24093860, 26507537, 30297972, 28255936, 32880476, 33025817, 30763825). Eight other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6), likely benign (n=1), or benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 25, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in at least 2 individuals, low frequency in ExAC, no segs - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2024 | Reported in association with HCM and DCM (PMID: 24093860, 22958901, 26507537, 32880476); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies using stem cells suggest that this variant does not impact protein function (PMID: 33025817); This variant is associated with the following publications: (PMID: 26507537, 28255936, 32880476, 30763825, 33025817, 24093860, 30297972, 22958901) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 12, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 221 of the TNNT2 protein (p.Ile221Thr). This variant is present in population databases (rs45520032, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 24093860, 26507537, 32880476). ClinVar contains an entry for this variant (Variation ID: 181604). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TNNT2 function (PMID: 33025817). 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. - |
Dilated cardiomyopathy 1D Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine (exon 13). (N) 0251 - Variant is heterozygous. (N) 0308 - Population frequency for this variant is out of keeping with known incidence of DCM (45 heterozygotes, 0 homozygotes). (B) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. (Troponin coiled-coiled; PDB) (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. (N) p.Ile228Val reported VUS in two individuals (ClinVar). 0808 - Previous reports of pathogenicity are conflicting. (N) Reported as VUS in four individuals and likely benign in one individual (ClinVar), one patient with ARVC and DCM (Te Rijdt, W. et al (2019)), two HCM patients (Marsiglia, J. et al. (2013), Ripoll-Vera, T. et al. (2016)), one sudden death patient (Campuzano, O. et al. (2017)). 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 31, 2018 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BP6. - |
Hypertrophic cardiomyopathy 2 Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 25, 2022 | This missense variant replaces isoleucine with threonine at codon 221 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 26507537, 33495596), as well as in an individual affected with arrhythmogenic right ventricular cardiomyopathy ARVC and dilated cardiomyopathy who also carried a pathogenic truncation variant in the PLN gene (PMID: 30763825). This variant has also been identified in 45/282870 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Dilated Cardiomyopathy, Dominant Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Left ventricular noncompaction cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiomyopathy, familial restrictive, 3 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;.;D;.;.;.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
.;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;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;.;.;.;.;.;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;.;.;D;D;D
Sift4G
Uncertain
D;T;D;D;D;T;D;T;D;D;.
Polyphen
0.98
.;.;.;.;D;.;.;.;.;.;.
Vest4
MVP
MPC
1.1
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at