chr1-201361327-C-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BS1BS2
The NM_001276345.2(TNNT2):c.762G>T(p.Glu254Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001276345.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000223 AC: 56AN: 251480Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135914
GnomAD4 exome AF: 0.000205 AC: 299AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 139AN XY: 727240
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:5
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. -
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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) -
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Cardiomyopathy Uncertain:3
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. -
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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. -
Dilated cardiomyopathy 1D Uncertain:2
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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 -
Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Uncertain:2
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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. -
not specified Uncertain:1Benign:1
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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. -
TNNT2-Related Cardiomyopathy Uncertain:1
The TNNT2 c.732G>T (p.Glu244Asp) missense variant has been reported in at least four studies in which it is found in a heterozygous state in three probands (Watkins et al. 1995; Hershberger et al. 2009; Rampersaud et al. 2011; Viswanathan et al. 2017). Two of the probands were diagnosed with hypertrophic cardiomyopathy and the third proband with dilated cardiomyopathy (DCM). The proband affected with DCM also carried a second missense variant in the TMP1 gene (Hershberger et al. 2010). The p.Glu244Asp variant was absent from at least 800 control chromosomes (Hershberger et al. 2009; Hershberger et al. 2010; Rampersaud et al. 2011) and is reported at a frequency of 0.000599 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of p.Glu244Asp in bovine and rabbit cardiac myofibrils showed an enhanced maximum level of ATPase activity with no significant difference in calcium ion sensitivity (Yanaga et al. 1999; Matsumoto et al. 2009; Willott et al. 2009). Based on the evidence, the p.Glu244Asp variant is classified as a variant of unknown significance but suspicious for pathogenicity for TNNT2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Hypertrophic cardiomyopathy 2 Uncertain:1
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Cardiovascular phenotype Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at