Submissions for variant NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr)

gnomAD frequency: 0.00015  dbSNP: rs45520032

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001529098	SCV000209209	uncertain significance	not provided	2024-04-23	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230425	SCV000285655	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2025-01-22	criteria provided, single submitter	clinical testing	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, 33495596, 37198425, 37652022). ClinVar contains an entry for this variant (Variation ID: 181604). 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) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. 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.
Illumina Laboratory Services, Illumina	RCV000986503	SCV000353328	uncertain significance	Hypertrophic cardiomyopathy 2	2018-01-13	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000378147	SCV000353329	uncertain significance	Cardiomyopathy, familial restrictive, 3	2018-01-13	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000283636	SCV000353330	uncertain significance	Left ventricular noncompaction cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000338870	SCV000353331	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168973	SCV000540564	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	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
Ambry Genetics	RCV000619781	SCV000737050	likely benign	Cardiovascular phenotype	2023-08-14	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000986503	SCV001135516	benign	Hypertrophic cardiomyopathy 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182244	SCV001347631	uncertain significance	Cardiomyopathy	2022-11-25	criteria provided, single submitter	clinical testing	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196994	SCV001367629	uncertain significance	Dilated cardiomyopathy 1D	2018-10-31	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168973	SCV002600704	uncertain significance	not specified	2023-05-23	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001196994	SCV002768616	likely benign	Dilated cardiomyopathy 1D	2020-05-21	criteria provided, single submitter	clinical testing	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
Fulgent Genetics, Fulgent Genetics	RCV000230425	SCV005633648	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-02-07	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529098	SCV001968580	uncertain significance	not provided		no assertion criteria provided	clinical testing