Submissions for variant NM_000159.4(GCDH):c.262C>A (p.Arg88Ser)

dbSNP: rs142967670

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634887	SCV000756253	pathogenic	Glutaric aciduria, type 1	2023-08-16	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg88 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 23395213, 24332224, 28438223). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCDH protein function. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 88 of the GCDH protein (p.Arg88Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with glutaric aciduria, type I (PMID: 27397597; Invitae). ClinVar contains an entry for this variant (Variation ID: 529444).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000634887	SCV001360426	likely pathogenic	Glutaric aciduria, type 1	2023-03-16	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.262C>A (p.Arg88Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes (gnomAD). c.262C>A has been reported in the literature in an individual affected with Glutaric Acidemia Type 1 (example: Schillaci_2016). Variants at the same codon position as the variant of interest but causing different amino acid changes (i.e. c.262C>T, p.Arg88Cys, classified pathogenic in our internal database; c.263G>A, p.Arg88His) have been reported in multiple affected individuals (Schmiesing_2017, Wang_2014). Schmiesing et al. (2017) carried out functional assessment of the p.Arg88Cys and other variants resulting in different amino acid substitutions at position 88 of the protein sequence, and concluded that Arg88 is essential for preserving mitochondrial architecture and GCDH activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000634887	SCV002018413	likely pathogenic	Glutaric aciduria, type 1	2021-07-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000634887	SCV004191004	pathogenic	Glutaric aciduria, type 1	2023-10-10	criteria provided, single submitter	clinical testing