Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001906933 | SCV002177893 | uncertain significance | D-2-hydroxyglutaric aciduria 2 | 2021-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 393 of the IDH2 protein (p.Arg393Lys). This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IDH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Clinical Genomics Laboratory, |
RCV001906933 | SCV005685284 | uncertain significance | D-2-hydroxyglutaric aciduria 2 | 2024-08-21 | criteria provided, single submitter | clinical testing | The IDH2 c.1178G>A (p.Arg393Lys) variant was identified at a near heterozygous allelic fraction of 47.8%, a frequency which may be consistent with it being of germline origin. This variant, to our knowledge, has not been reported in the medical literature. This variant is only observed on 1/1,613,864 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. This variant has been reported in the ClinVar database as a variant of uncertain significance by one submitter (ClinVar ID: 1406554). Computational predictors suggest that the variant does not impact IDH2 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the IDH2 c.1178G>A (p.Arg393Lys) variant is uncertain at this time. |