Submissions for variant NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)

dbSNP: rs397516470

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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members, and was abs ent from 700 control chromosomes (Watkins 1995, Palm 2001, Richard 2003, Torrice lli 2003, LMM unpublished data).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 (http://www.partners.org/personalizedmedicine/LMM) base d on segregation studies and absence from controls.
GeneDx	RCV000624557	SCV000209278	pathogenic	not provided	2022-05-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies in E. coli demonstrated p.(E163del) (reported as deltaE160) resulted in recombinant troponin with increased calcium ion sensitivity (Messer et al., 2016); Published functional studies using transgenic mice demonstrated that the del160E (c.487_489delGAG) variant leads to cellular hypertrophy and myofilament disarray as well as impairments in contraction, relaxation, and calcium handling (Moore et al., 2013; Moore et al., 2014); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14654368, 22579624, 22144547, 7898523, 28771489, 12746413, 31589614, 33673806, 33025817, 21835320, 23054336, 20800588, 25558701, 12707239, 20624503, 24480310, 27662471, 27639548, 26688388, 16538283, 27532257, 28214152, 24792744, 26714042, 31006259, 31308319, 31387947, 22260945, 14636924, 11606294, 10731693, 33906374, 23434821, 27036851)
Invitae	RCV000459834	SCV000541933	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-28	criteria provided, single submitter	clinical testing	This variant, c.487_489del, results in the deletion of 1 amino acid(s) of the TNNT2 protein (p.Glu163del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (HCM) and restricted cardiomyopathy (RCM) (PMID: 7898523, 20624503, 22144547, 22260945, 24792744). It has also been observed to segregate with disease in related individuals. This variant is also known as DeltaE160. ClinVar contains an entry for this variant (Variation ID: 43648). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TNNT2 function (PMID: 10731693, 22579624, 24480310, 27036851). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000620577	SCV000739945	pathogenic	Cardiovascular phenotype	2021-01-28	criteria provided, single submitter	clinical testing	The c.487_489delGAG pathogenic mutation (also known as p.E163del) is located in coding exon 10 of the TNNT2 gene. This alteration results from an in-frame deletion of 3 nucleotides at positions 487 to 489, causing the removal of a well-conserved glutamic acid residue at codon 163. Strong segregation of this alteration, also described as ΔGlu160, with hypertrophic cardiomyopathy has been demonstrated (Watkins H et al. N Engl J Med. 1995;332(16):1058-64). This alteration has also been detected in patients reported to have restrictive cardiomyopathy (Walsh MA et al. Circ Heart Fail. 2012;5(2):267-73). Additionally, a combination of in vitro and in vivo studies showed disrupted weak electrostatic actomyosin binding in motility assays and severe cardiac remodeling and myofilament disarray in transgenic mice (Moore RK et al. Arch Biochem Biophys. 2014;552-553:21-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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
AiLife Diagnostics, AiLife Diagnostics	RCV000624557	SCV002501176	likely pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211867	SCV004839106	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid at exon 11 of the tropomyosin binding domain 1 in the TNNT2 protein. In-vivo functional studies using a transgenic mouse knock-in model have shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy, including sarcomeric abnormalities, cellular hypertrophy, decreased calcium uptake activity, and myofilament disarray (PMID: 23434821, 24480310, 26714042). Additional in-vitro functional studies using transfected porcine cardiac myofibrils have shown that this variant causes altered troponin affinity and increased calcium sensitivity (PMID: 10731693) . This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 12707239, 14636924, 20800588, 21835320, 22144547, 24792744, 25611685, 27639548, 28771489, 28790153, 27532257, 31308319, 33029862, 33673806). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 7898523, 14636924). This variant has been reported to occur de novo in one individual affected with hypertrophic cardiomyopathy (PMID: 25611685). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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; http://gnomad.broadinstitute.org/), 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000624557	SCV001929709	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000624557	SCV001953581	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Cardiology unit, Meyer University Hospital	RCV002286700	SCV002577349	likely pathogenic	Hypertrophic cardiomyopathy 2	2022-09-27	no assertion criteria provided	clinical testing