ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.866G>A (p.Gly289Glu) (rs727505233)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000156740 SCV000206461 uncertain significance not specified 2014-08-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Gly279Glu v ariant in TNNT2 has not been reported in individuals with cardiomyopathy or in l arge population studies. This variant was predicted to be pathogenic using a com putational tool clinically validated by our laboratory. This tool's pathogenic p rediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance o f the Gly279Glu variant is uncertain.
GeneDx RCV000481381 SCV000565619 likely pathogenic not provided 2015-03-01 criteria provided, single submitter clinical testing A novel G279E variant that is likely pathogenic was identified in the TNNT2 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G279E variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The G279E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R278C, R278P, R278H, K280N, R286C, R286P, R286H) have been reported in the Human Gene Mutation Database in association with hypertrophic cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV001327654 SCV001518739 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-03-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 279 of the TNNT2 protein (p.Gly279Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179939). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000156740 SCV000280533 uncertain significance not specified 2015-03-05 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly279Glu (c.836T>A) in the TNNT2 gene (NM_001001430.1) The variant has been seen in at least one case of HCM (not including this patient's family). LMM has reported this variant in clinvar in one individual with HCM (at the time of review). They report the following: "The Gly279Glu variant in TNNT2 has not been reported in individuals with cardiomyopathy or in large population studies. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Gly279Glu variant is uncertain." In silico analysis with HCM PolyPhen-2 predicts the variant to be pathogenic. The Gly at codon 279 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (R278C, R278P, R278H, K280N, R286C, R286P, R286H). In total the variant has not been seen in published controls and individuals from publicly available population datasets. There is no variation at codon 1836 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on 6500 Caucasian and African American individuals (as of April 8, 2015). Note that this dataset does not match the patient's ancestry (Indian). There is one individual with variation at codon 279 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 8, 2015). There also happens to be missense variation at codon 278 (42 individuals with missense variants).

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