Submissions for variant NM_000159.4(GCDH):c.482G>A (p.Arg161Gln)

gnomAD frequency: 0.00001  dbSNP: rs777201305

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725818	SCV000339588	pathogenic	not provided	2016-02-09	criteria provided, single submitter	clinical testing
Invitae	RCV000169118	SCV000961335	pathogenic	Glutaric aciduria, type 1	2023-08-04	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 161 of the GCDH protein (p.Arg161Gln). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GCDH function (PMID: 28062662). 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 not expected to disrupt GCDH protein function. ClinVar contains an entry for this variant (Variation ID: 188789). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 10960496, 20836999, 26593172, 28781846). This variant is present in population databases (rs777201305, gnomAD 0.006%).
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000169118	SCV001430116	pathogenic	Glutaric aciduria, type 1	2019-06-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169118	SCV001521163	pathogenic	Glutaric aciduria, type 1	2020-05-05	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000169118	SCV002024219	pathogenic	Glutaric aciduria, type 1	2020-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169118	SCV002547876	pathogenic	Glutaric aciduria, type 1	2022-05-13	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.482G>A (p.Arg161Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251394 control chromosomes. c.482G>A has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Glutaric Acidemia Type 1 (example, Popek_2010, Busquets_2000, Christensen_2004, Wang_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Schmiesing_2017). The most pronounced variant effect results in loss of normal GCDH enzyme activity. The variant was also demonstrated to affect GCDH protein stability, protein homo-oligomerization and binding to electron transfer flavoprotein subunit -beta (ETFB) and dihydrolipoamide S-succinyltransferase (DLST), thereby impairing the formation of multimeric enzyme complexes. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169118	SCV002779438	likely pathogenic	Glutaric aciduria, type 1	2022-04-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169118	SCV004804656	pathogenic	Glutaric aciduria, type 1	2024-03-17	criteria provided, single submitter	research
Counsyl	RCV000169118	SCV000220321	pathogenic	Glutaric aciduria, type 1	2019-06-06	no assertion criteria provided	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000169118	SCV000537797	pathogenic	Glutaric aciduria, type 1		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169118	SCV002086966	pathogenic	Glutaric aciduria, type 1	2021-01-05	no assertion criteria provided	clinical testing