Submissions for variant NM_000159.4(GCDH):c.881G>A (p.Arg294Gln)

gnomAD frequency: 0.00005  dbSNP: rs775606471

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001066080	SCV001231075	pathogenic	Glutaric aciduria, type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 294 of the GCDH protein (p.Arg294Gln). This variant is present in population databases (rs775606471, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 15505393, 29665094). ClinVar contains an entry for this variant (Variation ID: 859875). 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: 9600243, 15505393, 25762492, 29201125; Invitae). 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	RCV001066080	SCV002500573	pathogenic	Glutaric aciduria, type 1	2022-03-22	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.881G>A (p.Arg294Gln) results in a conservative amino acid change in 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 1.2e-05 in 250556 control chromosomes. c.881G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that GCDH activity was not detected in fibroblasts from the patient with homozygous R294Q. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV001066080	SCV002516456	pathogenic	Glutaric aciduria, type 1	2022-05-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001066080	SCV004199220	pathogenic	Glutaric aciduria, type 1	2024-01-11	criteria provided, single submitter	clinical testing
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV001066080	SCV004800902	likely pathogenic	Glutaric aciduria, type 1		no assertion criteria provided	clinical testing	PM2_P+PM3_S+PP3+PP4