ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.508_510GAG[3] (p.Glu173del) (rs397516470)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211867 SCV000060251 pathogenic Hypertrophic cardiomyopathy 2012-10-08 criteria provided, single submitter clinical testing The p.Glu163del variant in TNNT2 has been previously reported in multiple famili es with HCM, segregated with disease in >10 affected family members, and was abs ent from 700 control chromosomes (Watkins 1995, Palm 2001, Richard 2003, Torrice lli 2003, LMM unpublished data). Functional studies indicate that this variant m ay impact protein function (Tobacman 1999, Harada 2000, Manning 2012), though th ese in vitro assays may not accurately represent biological function. In summary , this variant meets our criteria to be classified as pathogenic for HCM in an a utosomal dominant manner ( base d on segregation studies and absence from controls.
Invitae RCV000459834 SCV000541933 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-26 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 11 of the TNNT2 mRNA (c.487_489delGAG). This leads to the deletion of 1 amino acid residue in the TNNT2 protein (p.Glu163del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) and restricted cardiomyopathy (RCM) (PMID: 7898523, 22144547, 20624503, 22260945), being found to segregate with HCM in three families  (PMID: 24792744). This variant is also known as DeltaE160 in the literature. ClinVar contains an entry for this variant (Variation ID: 43648). Experimental studies have shown that this variant reduces the interaction of troponin T with tropomyosin, leading to an increase in the Ca2+ sensitivity of the myofibrillar ATPase activity (PMID: 10731693, 22579624, 24480310, 27036851). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620577 SCV000739945 pathogenic Cardiovascular phenotype 2017-07-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Significant disease association in appropriately sized case-control study(ies),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624557 SCV000740431 pathogenic not provided 2016-11-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000624557 SCV000927600 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000624557 SCV000924966 pathogenic not provided 2017-04-12 no assertion criteria provided provider interpretation Testing for our patients was performed at the Invitae laboratory. Given the strong case data, supportive functional studies, and absence in general population databases, we consider this variant very likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant is also referenced in the literature as DeltaE160. The variant has been published in at least 8 unrelated cases of HCM and 3 unrelated cases of RCM (not including this patient's family). We have seen this variant in two patients with HCM at our center. Many of the published families have several affected family members who carry the variant. There is additional case data and strong segregation data have been reported by genetic testing laboratories. The unrelated case count is a conservative estimate, however it is difficult to discern independent cases since few of the published cases report where genetic testing was done and overlapping authors. Presumably some of the original cases published by Watkins in 1995 overlap with cases documented by testing laboratories. Watkins et al. (1995) first reports this variant in patients with HCM. They report the variant was observed in 32 individuals from two families (includes those identified by screening, those deduced from pedigree, and some deceased individuals). However, only 14 of those individuals were studied clinically. 14 of the 32 individuals died suddenly. Average maximum wall thickness was 17.5mm. Study was done at Harvard. Richard et al (2003) report this variant in one index patient with HCM (recruited in France). HCM diagnostic criteria for the study included wall thickness >1.3cm or major abnormalities on ECG. Torricelli et al (2003) reports the variant in three affected individuals of one family (proband, brother, nephew) with HCM. These individuals were recruited from Tuscany. Millat et al. (2010) report this variant in one affected proband with HCM. Patients were French. While possibly an overlapping case with Richard et al, the authors do not appear to overlap. Pasquale et al (2012) refers to the variant as Delta163. The authors observed the variant in 3 families, with 27 carriers. Cases may overlap with those from Watkins et al. There was no specific clinical data for the individuals with the variant, although they all had HCM. Walsh et al. (2012) report this variant in a proband with RCM diagnosed at 17yo and another with RCM diagnosed at 16yo. Maron et al (2014) reports this variant in a brief case report of a family with HCM and RCM (see pedigree below). The authors report that this variant was associated with several phenotypes: non-dilated LV with segmental hypertrophy (no measurements) and intact systolic function, end stage HCM with LV remodeling and systolic dysfunction, and "restrictive" form with impaired ejection fraction. Individual III-4 had non obstructive HCM, anterior ventricular septum measuring 2.3cm, and EF 53% at 37yo. Individual III-2 had non obstructive HCM, posterior ventricular septum measuring 2.1cm and EF of 75% at 28yo. Individual II-1 had a progressive heart failure requiring transplantation at 54yo. He also had history of 2 cardiac arrests, EF of 30% and LVEDD of 5.2cm. Individual II-5 is a 67yo with heart failure requiring transplantation at age 61. She had a restrictive phenotype, LV wall was normal thickness, and EF of 40%. It is unclear from the pedigree if these individuals are all from one family or separate families. The authors also do not include clinical information on those individuals who have tested negative (II-6, III-5, and III-6). The glutamine at codon 163 is conserved across species. The variant falls within the hinge-flexible loop domain and several functional studies have been done to investigate the functional effect of this single amino acid deletion. Harada et al. (2000) report that "the mutant troponin T showed a slightly reduced potency in replacing the endogenous troponin complex in myofibrils and did not affect the inhibitory action of troponin I but potentiated the neutralizing action of troponin C, suggesting that the deletion of a single amino acid, Glu-160, in the strong tropomyosin-binding region affects the tropomyosin binding affinity of the entire troponin T molecule and alters the interaction between troponin I and troponin C within ternary troponin complex in the thin filament. This mutation also increased the Ca(2+) sensitivity of the myofibrillar ATPase activity, as in the case of other mutations in troponin T with clinical phenotypes of poor prognosis similar to that of Glu160." Manning et al (2012) found that this variant results in a decrease in flexibility of the troponin T protein, which results in a tightening of the helix at the C-terminus of TNT1 that both stiffens TNT1 and pulls on the cTnT linker. This results in dramatically different physical behavior. Moore et al (2014) evaluated the in vivo effects of this variant in mutant mice. Severe, progressive cardiac remodeling and myofilament disarray were observed in vivo. In vitro motility assays were consistent with weaker electrostatic binding conditions and increased calcium sensitivity. Messer et al (2016) also replicated increased calcium sensitivity in vitro in troponin T protein harboring this variant. The variant is not present in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >123,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 95x.

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