ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.277G>A (p.Glu93Lys) (rs727504244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000225724 SCV000209221 likely pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing A missense variant that is likely pathogenic was identified in the TNNT2 gene. The E83K variant has been published several times in association with HCM (Mogensen et al., 2003; Pasquale et al., 2012; Walsh et al., 2017). This variant has also been identified independently in multiple unrelated individuals affected with HCM referred for genetic testing at GeneDx; however, segregation data is currently limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The E83K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E83K 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. Moreover, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, a missense variant in the same residue (E83D), as well as multiple missense variants in nearby residues (I79T, I79N, P80S, G82R, R84T, R84S, V85L, D86A, F87C), have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.
Invitae RCV001300619 SCV001489765 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 83 of the TNNT2 protein (p.Glu83Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 22144547, 27532257). ClinVar contains an entry for this variant (Variation ID: 177632). Algorithms developed to predict the effect of missense changes on protein structure and function 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154214 SCV000203867 uncertain significance not specified 2014-10-29 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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