ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.680G>C (p.Arg227Pro)

gnomAD frequency: 0.00026  dbSNP: rs121434373
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000078256 SCV000232475 pathogenic not provided 2012-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000078256 SCV000321706 pathogenic not provided 2020-07-06 criteria provided, single submitter clinical testing Published functional studies demonstrate a reduction in glutaryl-CoA dehydrogenase enzyme activity by more than 95% (Biery et al., 1996); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11073722, 9600243, 15505393, 28794906, 22728054, 25087612, 10699052, 10960496, 8900227, 28062662, 28438223, 10066389, 9266361, 10384381, 27397597, 18683078, 20629163, 23395213, 29458885, 30570710, 31491587, 12872844, 31589614)
Illumina Laboratory Services, Illumina RCV000002170 SCV000410865 pathogenic Glutaric aciduria, type 1 2017-11-29 criteria provided, single submitter clinical testing The GCDH c.680G>C (p.Arg227Pro) variant has been identified in at least 20 individuals with glutaric acidemia, including in a homozygous state in two individuals and in a compound heterozygous state in 18 individuals (Biery et al. 1996; Christensen et al. 1997; Busquets et al. 2000a; Busquets et al. 2000b; Zschocke et al. 2000; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010; Couce et al. 2013). The p.Arg227Pro variant was absent from 400 controls but is reported at a frequency of 0.00026 in the Latino population of the Exome Aggregation Consortium. Functional studies demonstrated that p.Arg227Pro variant is associated with low residual activity of glutaryl-CoA dehydrogenase (GCDH) compared to wildtype (Biery et al. 1996; Christensen et al. 1997; Liesert et al. 1999; Bijarnia et al. 2008; Flamand-Rouviere et al. 2010). Additionally, the p.Arg227Pro variant was associated with atypical excretion of glutarate and 3-hydroxygluaratein urine analysis (Busquet et al. 2000a; Busquet et al. 2000b; Zschocke et al. 2000; Couce et al. 2013). Based on the collective evidence, the p.Arg227Pro variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002170 SCV000695722 pathogenic Glutaric aciduria, type 1 2017-08-02 criteria provided, single submitter clinical testing Variant summary: The GCDH c.680G>C (p.Arg227Pro) variant, located in the beta-sandwich in close proximity to FAD, involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Biery_1996, supports these predictions with the observed significant decrease in GCDH activity. This variant was found in 21/121390 control chromosomes at a frequency of 0.000173, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). Multiple publications have reported this variant in affected individuals presenting with mild to severe phenotypes, including two affected siblings. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.
Invitae RCV000002170 SCV000756255 pathogenic Glutaric aciduria, type 1 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 227 of the GCDH protein (p.Arg227Pro). This variant is present in population databases (rs121434373, gnomAD 0.04%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 9266361, 10066389, 10960496, 11073722, 22728054, 23395213, 28438223). ClinVar contains an entry for this variant (Variation ID: 2089). 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%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000002170 SCV000894186 pathogenic Glutaric aciduria, type 1 2022-01-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002170 SCV001163446 pathogenic Glutaric aciduria, type 1 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000002170 SCV001194135 pathogenic Glutaric aciduria, type 1 2019-12-20 criteria provided, single submitter clinical testing NM_000159.2(GCDH):c.680G>C(R227P) is classified as pathogenic in the context of glutaric acidemia, GCDH-related. Sources cited for classification include the following: PMID 8900227, 10960496, 10384381, 29665094, 11015709, 22728054, 30570710, 12872844 and 9266361. Classification of NM_000159.2(GCDH):c.680G>C(R227P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity Omics RCV000002170 SCV002024220 pathogenic Glutaric aciduria, type 1 2023-10-27 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000078256 SCV002064440 pathogenic not provided 2019-03-06 criteria provided, single submitter clinical testing DNA sequence analysis of the GCDH gene demonstrated a sequence change, c.680G>C, in exon 8 that results in an amino acid change, p.Arg227Pro. This sequence change has been previously described in patients with glutaryl-CoA dehydrogenase (GCDH) deficiency in the homozygous and the compound heterozygous state (PMIDs: 10066389, 23395213, 9266361). This variant also showed reduced GCD activity by >95% when expressed in E coli (PMID: 8900227). This sequence change has been described in the gnomAD database with a low population frequency of 0.019% (dbSNP rs121434373). The p.Arg227Pro change affects a moderately conserved amino acid residue located in a domain of the GCDH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg227Pro substitution.
OMIM RCV000002170 SCV000022328 pathogenic Glutaric aciduria, type 1 1996-11-01 no assertion criteria provided literature only
GeneReviews RCV000002170 SCV001133276 not provided Glutaric aciduria, type 1 no assertion provided literature only Low-excreter; 85%-10% residual activity
Natera, Inc. RCV000002170 SCV001456389 pathogenic Glutaric aciduria, type 1 2020-09-16 no assertion criteria provided clinical testing

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