ClinVar Miner

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

gnomAD frequency: 0.00005  dbSNP: rs775606471
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Total submissions: 5
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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.
Illumina Laboratory Services, Illumina RCV001066080 SCV001286372 uncertain significance Glutaric aciduria, type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
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 2023-08-21 criteria provided, single submitter clinical testing

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