ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.753G>T (p.Glu251Asp) (rs45466197)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036615 SCV000060270 uncertain significance not specified 2017-04-28 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 unspecif ied ancestry with HCM (Watkins 1995) and one individual of African American ance stry with DCM who carried another variant of unknown significance in the TPM1 ge ne (Hershberger 2008, Hershberger 2009, Hershberger 2010, Rampersaud 2011), and has been reported in ClinVar (Variation ID#43667). This variant has been identif ied in 3 individuals with cardiomyoopathy tested by our laboratory, one of whom carries a second likely disease-causing variant and had an early onset of diseas e, and a second who had an additional TNNT2 variant of uncertain significance an d 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 t he 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 2 009), but it has not been demonstrated whether this can result in disease. The p resence 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 th is variant in addition to a second variant, it is possible that it is exacerbati ng disease severity in these cases. In summary, additional data is need to inter pret the pathogenicity of this variant for causing primary disease as well as wh ether it may play a role in modifying the severity of disease due to other cause s.
CSER_CC_NCGL; University of Washington Medical Center 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 2018-01-19 criteria provided, single submitter clinical testing The E244D variant of uncertain significance in the TNNT2 gene has been reported previously in association with HCM (Watkins et al., 1995; Hershberger et al., 2008; Yanaga et al., 1999; Harada et al., 2004; Matsumoto F et al., 2009). Watkins et al. (1995) and Hershberger et al. (2008) each identified E244D in one individual with HCM, while it was absent from >253 control individuals (Watkins et al 1995; Hershberger et al., 2008). In addition, the E244D variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Additionally, this variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx. However, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Although E244D results in a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position in the coiled-coil region of the cardiac troponin T core domain that is highly conserved (Watkins et al., 1995). Furthermore, multiple functional studies report that the E244D variant and other missense substitutions at this codon increase the maximum level of myosin ATPase activity without altering calcium sensitivity (Yanaga et al., 1999; Harada et al., 2004; Matsumoto et al., 2009). Nevertheless, it is classified in ClinVar as a variant of uncertain significance by one clinical laboratory and as a likely benign variant by a second clinical laboratory (ClinVar SCV000060270.4, SCV000264255.1; Landrum et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. Clinical correlation with this test result is recommended.
Blueprint Genetics RCV000036615 SCV000264255 likely benign not specified 2015-04-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415651 SCV000493812 uncertain significance Left ventricular noncompaction 6 2015-12-19 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000415695 SCV000493813 uncertain significance Familial hypertrophic cardiomyopathy 2 2015-12-19 criteria provided, single submitter clinical testing
Color RCV000777715 SCV000913659 uncertain significance Cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the tropomyosin binding domain of the TNNT2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that the variant does not cause changes in Ca2+ sensitivity of force development but increase maximal force development (PMID: 10085122, 10467159, 14722098, 19293840). Clinical significance of these findings is not clear. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 7898523), as well as in individuals affected with dilated cardiomyopathy (PMID: 19412328, 20031601, 21483645). This variant has also been identified in 59/126688 non-Finnish European chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Illumina Clinical Services Laboratory,Illumina RCV000778959 SCV000915386 uncertain significance TNNT2-Related Cardiomyopathy 2018-04-20 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000793380 SCV000932728 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 244 of the TNNT2 protein (p.Glu244Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs45466197, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 29121657) and in an individual with dilated cardiomyopathy (PMID: 19412328). ClinVar contains an entry for this variant (Variation ID: 43667). Experimental studies have shown that this missense change increases ATPase activity withouth changing calcium sensitivity of the TNNT2 protein (PMID: 19275886, 10085122, 14722098). 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.

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