Submissions for variant NM_001276345.2(TNNT2):c.762G>T (p.Glu254Asp)

gnomAD frequency: 0.00007  dbSNP: rs45466197

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000225695	SCV000060270	uncertain significance	not provided	2019-04-04	criteria provided, single submitter	clinical testing	The p.Glu244Asp variant (NM_001001430.1 c.732G>T; also referred to as NM_000364.3 c.753G>T p.Glu251Asp) in TNNT2 has been reported in one individual of unspecified ancestry with HCM (Watkins 1995) and one individual of African American ancestry with DCM who carried another variant of unknown significance in the TPM1 gene (Hershberger 2008, Hershberger 2009, Hershberger 2010, Rampersaud 2011), and has been reported in ClinVar (Variation ID#43667). This variant has been identified in 3 individuals with cardiomyopathy tested by our laboratory, one of whom carries a second likely disease-causing variant and had an early onset of disease, and a second who had an additional TNNT2 variant of uncertain significance and an early onset of disease. This variant has been identified in 0.06% (40/66740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45466197). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In vitro studies have shown that the p.Glu244Asp variant may impact protein function (Watkins 1995, Yanaga 1995, Harada 2004, Matsumoto 2009), but it has not been demonstrated whether this can result in disease. The presence of a variant in HCM and DCM probands raises suspicion about its clinical significance as the two cardiomyopathies are caused by different defects at the cellular level. Given the early onset of disease in all individuals carrying this variant in addition to a second variant, it is possible that it is exacerbating disease severity in these cases. In summary, additional data is need to interpret the pathogenicity of this variant for causing primary disease as well as whether it may play a role in modifying the severity of disease due to other causes.
CSER _CC_NCGL, University of Washington	RCV000148901	SCV000190647	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx	RCV000225695	SCV000209257	uncertain significance	not provided	2024-11-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7898523, 19412328, 28352236, 23299917, 19293840, 20215591, 19473338, 29121657, 14722098, 20031601, 25637381, 19275886, 10085122, 26774798, 27493864, 21483645, 30565988, 33025817, 10467159, 32429250, 30847666, 37937776, 37652022, 36129056, 10497196)
Blueprint Genetics	RCV000036615	SCV000264255	likely benign	not specified	2015-04-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777715	SCV000913659	uncertain significance	Cardiomyopathy	2024-05-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 244 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Experimental functional studies have shown that the variant does not cause changes in Ca2+ sensitivity of force development but increases maximal force development (PMID: 10085122, 10467159, 14722098, 19293840). Clinical relevance of this observation is not clear. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 30565988), in three individuals affected with dilated cardiomyopathy (PMID: 19412328, 20031601, 21483645), and in one individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has been identified in 58/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000036615	SCV000920314	uncertain significance	not specified	2018-09-11	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.732G>T (p.Glu244Asp) results in a 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 0.00021 in 277176 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.00047 in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNNT2 causing Cardiomyopathy phenotype (0.00018), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.732G>T has been reported in the literature in one individual affected with Hypertrophic Cardiomyopathy (Watkins 1995) and in another individual with Dilated Cardiomyopathy, who also had another variant of unknown significance in the TPM1 gene (Hershberger 2008, Hershberger 2009, Rampersaud 2011). In none of these cases were the variant shown to be present in family members. Therefore these reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Several publications reported experimental evidence evaluating an impact on protein function. Multiple studies found that the variant protein increased the maximum level of ATPase activity with either increasing (Nakaura 1999) or not affecting Ca2+ sensitivity (Yanaga 1999, Harada 2004, Matsumoto 2009). A further study demonstrated that the variant caused abnormal troponin function, i.e. impaired troponin binding to the thin filament (Tobacman 1999) and disturbed the protein conformation (Matsuo 2015). However, it is unclear how these changes can result in disease. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (2x), Likely benign (1x), Likely pathogenic (1x)). Based on the evidence outlined above, the variant was classified as uncertain significance, until additional evidence becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793380	SCV000932728	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 244 of the TNNT2 protein (p.Glu244Asp). This variant is present in population databases (rs45466197, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 7898523, 19412328, 29121657, 30565988, 37652022). This variant is also known as E251D, E254D. ClinVar contains an entry for this variant (Variation ID: 43667). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 10085122, 10467159, 10497196, 14722098, 19275886, 30565988). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777715	SCV001333651	uncertain significance	Cardiomyopathy	2023-05-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381298	SCV002668839	likely benign	Cardiovascular phenotype	2021-05-07	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000415651	SCV002768310	uncertain significance	Dilated cardiomyopathy 1D	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Functional studies have suggested loss-of-function, gain-of-function and dominant-negative mechanisms based on calcium sensitivity, contractibility and mouse models (PMID: 18612386, 32098556, 33025817). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (58 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated troponin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as likely benign, and many times as a VUS, in several individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy (ClinVar, LOVD, PMID: 30847666). In some of these individuals, additional variants in cardiac genes were found. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected bovine and porcine fibres have been shown to result in a slight increase in maximum ATPase activity, and significant increase in maximum force. The biological significance of these findings is unclear (PMID: 19275886, PMID: 14722098). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
All of Us Research Program, National Institutes of Health	RCV000777715	SCV004821974	uncertain significance	Cardiomyopathy	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 244 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have shown that the variant does not cause changes in Ca2+ sensitivity of force development but increases maximal force development (PMID: 10085122, 10467159, 14722098, 19293840). Clinical relevance of this observation is not clear. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 30565988), in individuals affected with dilated cardiomyopathy (PMID: 19412328, 20031601, 21483645), and in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has been identified in 58/282838 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant allele frequency is thought to be higher than expected for TNNT2-related disorders, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000225695	SCV005198820	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000793380	SCV005633641	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-29	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415651	SCV000493812	uncertain significance	Dilated cardiomyopathy 1D	2015-12-19	no assertion criteria provided	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415695	SCV000493813	uncertain significance	Hypertrophic cardiomyopathy 2	2015-12-19	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000225695	SCV001919318	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000225695	SCV001963330	uncertain significance	not provided		no assertion criteria provided	clinical testing