Submissions for variant NM_002168.4(IDH2):c.640G>A (p.Ala214Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490892	SCV004241474	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: IDH2 c.640G>A (p.Ala214Thr) results in a non-conservative amino acid change located in the Isopropylmalate dehydrogenase-like domain (IPR024084) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251348 control chromosomes in the gnomAD database, including 1 homozygote. To our knowledge, no occurrence of c.640G>A in individuals affected with D-2-hydroxyglutaric aciduria 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005100342	SCV005777224	uncertain significance	D-2-hydroxyglutaric aciduria 2	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 214 of the IDH2 protein (p.Ala214Thr). This variant is present in population databases (rs367982647, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with IDH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2691697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt IDH2 protein function with a negative predictive value of 80%. 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.