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

dbSNP: rs727505233

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	uncertain significance	not provided	2019-09-13	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 179939; Landrum et al., 2016)
Invitae	RCV001327654	SCV001518739	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 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). 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. 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"). 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).
Genome-Nilou Lab	RCV003453199	SCV004180489	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453200	SCV004180490	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453198	SCV004180491	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
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).