Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV000778606 | SCV000914916 | uncertain significance | D-2-hydroxyglutaric aciduria 1 | 2018-10-25 | criteria provided, single submitter | clinical testing | The D2HGDH gene is c.1256G>A (p.Arg419His) missense variant has been reported in a single study and is found in one individual with D-2-hydroxyglutaric aciduria in a homozygous state (Kranendijk et al. 2010). The p.Arg419His variant was absent from 210 control alleles and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Genome Aggregation Database. A functional assay using patient fibroblasts showed that the p.Arg419His variant causes a significant reduction of D-2-HGDH enzyme activity compared to a control (Kranendijk et al. 2010). The evidence for this variant is limited. The p.Arg419His variant is classified as a variant of unknown significance but suspicious for pathogenicity for D-2-hydroxyglutaric aciduria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Invitae | RCV000778606 | SCV002313107 | uncertain significance | D-2-hydroxyglutaric aciduria 1 | 2021-09-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 419 of the D2HGDH protein (p.Arg419His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199908032, ExAC 0.009%). This variant has been observed in individual(s) with D-2-hydroxyglutaric aciduria (PMID: 20020533). ClinVar contains an entry for this variant (Variation ID: 631854). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this variant affects D2HGDH function (PMID: 30908763, 33431826). 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. |