Submissions for variant NM_000159.4(GCDH):c.1157G>C (p.Arg386Pro)

dbSNP: rs398123190

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078248	SCV000110086	uncertain significance	not provided	2017-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV000812634	SCV000952954	pathogenic	Glutaric aciduria, type 1	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 386 of the GCDH protein (p.Arg386Pro). This variant is present in population databases (rs398123190, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of glutaric acidemia type I (PMID: 32778825; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92527). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg386 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058907, 15505393, 24332224, 27672653, 28143689). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000812634	SCV004030059	likely pathogenic	Glutaric aciduria, type 1	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1157G>C (p.Arg386Pro) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (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 1.2e-05 in 251466 control chromosomes (gnomAD). c.1157G>C has been reported in the literature in homozygous siblings affected with Glutaric Acidemia Type 1 (Shaik_2020). These data indicate that the variant is likely to be associated with disease. 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: 32778825, 36221165; DOI:10.1016/j.mgene.2020.100804). Two ClinVar submitters have assessed the variant since 2014: one submitter classified the variant as uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.