Submissions for variant NM_000159.4(GCDH):c.880C>T (p.Arg294Trp)

gnomAD frequency: 0.00001  dbSNP: rs1864390545

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001066990	SCV001232016	pathogenic	Glutaric aciduria, type 1	2024-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 294 of the GCDH protein (p.Arg294Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric acidemia type 1 (PMID: 9600243, 15505393; Invitae). ClinVar contains an entry for this variant (Variation ID: 860646). 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.Arg294 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15505393, 29665094). 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.
Baylor Genetics	RCV001066990	SCV004199272	pathogenic	Glutaric aciduria, type 1	2024-01-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001066990	SCV005203538	pathogenic	Glutaric aciduria, type 1	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.880C>T (p.Arg294Trp) 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 was absent in 250556 control chromosomes. c.880C>T has been reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Glutaric Acidemia Type 1 (example, Christensen_2004, Schwartz_1998, Campos-Garcia_2019), including at least 1 individual carrying a pathogenic variant in trans. These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.881G>A, p.Arg294Gln), supporting the critical relevance of codon 294 to GCDH protein function. At least one publication reports experimental evidence evaluating an impact on protein function. Enzyme activity in homozygous patient fibroblasts was undetectable (example, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 31788423, 15505393, 9600243). ClinVar contains an entry for this variant (Variation ID: 860646). Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV005256740	SCV005910992	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	GCDH: PM3:Strong, PM1, PM2, PM5