ClinVar Genomic variation as it relates to human health

Variant summary: GCDH c.1148G>A (p.Arg383His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes. c.1148G>A has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Kilavuz_2021, Ulmanova_2020, Goodman_1998). Additionally, other variants affecting the same codon (p.R383C (classified as pathogenic/likely pathogenic in ClinVar) and p.R383S) have been observed in patients with Glutaric Acidemia Type I (e.g. PMID: 33578440, 30203563) supporting functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9711871, 33578440, 33015233). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

ClinVar contains an entry for this variant (Variation ID: 555739). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 9711871). This variant is present in population databases (rs764608975, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 383 of the GCDH protein (p.Arg383His). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCDH protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg383 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15505393, 28438223, 30298489). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.