ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.692T>C (p.Ile231Thr) (rs45520032)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000168973 SCV000209209 likely benign not specified 2012-04-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000230425 SCV000285655 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 221 of the TNNT2 protein (p.Ile221Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs45520032, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant was reported in individuas affected with hypertrophic cardiomyopathy (PMID: 24093860, 26507537). ClinVar contains an entry for this variant (Variation ID: 181604). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 Clinical Services Laboratory,Illumina RCV000986503 SCV000353328 uncertain significance Familial 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 Clinical Services Laboratory,Illumina RCV000378147 SCV000353329 uncertain significance Familial restrictive cardiomyopathy 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 Clinical Services Laboratory,Illumina RCV000283636 SCV000353330 uncertain significance Cardiomyopathy, left ventricular noncompaction 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000338870 SCV000353331 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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 uncertain significance Cardiovascular phenotype 2018-11-01 criteria provided, single submitter clinical testing The p.I221T variant (also known as c.662T>C), located in coding exon 12 of the TNNT2 gene, results from a T to C substitution at nucleotide position 662. The isoleucine at codon 221 is replaced by threonine, an amino acid with similar properties. This alteration was detected in a patient from a hypertrophic cardiomyopathy cohort, and was also detected in a sudden death victim with variants in other cardiac-related genes (Marsiglia JD et al. Am Heart J. 2013;166(4):775-82; Campuzano O et al. Sports Med. 2017;47(10):2101-2115). This variant was also detected in an individual from a population-based cohort who was not indicated as having overt cardiovascular disease (Bick AG et al. Am J Hum Genet. 2012;91(3):513-9). This amino acid position is well conserved in available vertebrate species; however, threonine is the reference amino acid in other 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 variant remains unclear.
Mendelics RCV000986503 SCV001135516 benign Familial hypertrophic cardiomyopathy 2 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001182244 SCV001347631 uncertain significance Cardiomyopathy 2021-01-12 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 not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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), 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 Left ventricular noncompaction 6 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.

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