Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001043401 | SCV001207145 | uncertain significance | L-2-hydroxyglutaric aciduria | 2021-02-04 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Arg282 amino acid residue in L2HGDH. Other variant(s) that disrupt this residue have been observed in individuals with L2HGDH-related conditions (PMID: 20052767), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 been observed in the homozygous state in an individual diagnosed with L-2-hydroxyglutaric aciduria (L-2-HGA) (PMID: 18362286); this variant has also been observed in two siblings with L-2-HGA; however, a second mutation was not identified in these individuals (PMID: 26829733). This variant is present in population databases (rs765312282, ExAC 0.03%). This sequence change replaces arginine with glutamine at codon 282 of the L2HGDH protein (p.Arg282Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. |