ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.1204C>T (p.Arg402Trp) (rs121434369)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255833 SCV000225200 pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000255833 SCV000321707 pathogenic not provided 2020-07-08 criteria provided, single submitter clinical testing Functional studies in E.coli and BHK cells transfected with R402W mutant plamids demonstrated reduced GCDH enzyme expression as compared to wild type, and upon cross-linkage, the formation of homotetrameric GCDH was strongly impaired in the R402W mutants (Biery et al., 1996; Keyser et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9711871, 32056211, 10699052, 25087612, 8900227, 18775954, 10960496, 24973495, 25762492, 28438223, 28352331, 29292490, 30217722, 30570710, 31062211, 25256449, 10649503, 20732827, 31589614, 32777384, 32240488)
Illumina Clinical Services Laboratory,Illumina RCV000002166 SCV000410870 pathogenic Glutaric aciduria, type 1 2017-04-27 criteria provided, single submitter clinical testing The GCDH c.1204C>T (p.Arg402Trp) variant has been described in at least nine studies and is found in at least 63 individuals with glutaric acidemia, including 26 in a homozygous state, 18 in a compound heterozygous state, and nine in a heterozygous state (Biery et al. 1996; Schwartz et al. 1998; Busquets et al. 2000a; Busquets et al. 2000b; Busquets et al. 2000c; Zschocke et al. 2000; Fraidakis et al. 2014; Georgiou et al. 2014; Gupta et al. 2015). The variant is found in an additional 24 disease alleles of unknown zygosity (Biery et al. 1996; Zschocke et al. 2000). The p.Arg402Trp variant has been described as the most common variant in different populations being present in 10-20% of alleles in affected individuals (Zschocke et al. 2000; Fraidakis et al. 2014). The p.Arg402Trp variant was absent from 100 unrelated Spanish controls and is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Expression of the p.Arg402Trp variant in E.coli and cultured fibroblasts showed reduced GCD activity compared to wild type, with 3% and <1% residual activity, respectively (Biery et al. 1996; Busquets et al. 2000b; Schwartz et al. 1998). Keyser et al. (2008) also demonstrated a reduced enzyme activity for the variant of 1.6% of wild type in mammalian cells and an increased degradation of the protein compared to wild type. The Arg402 residue is highly conserved. Based on the collective evidence, the p.Arg402Trp 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 RCV000002166 SCV000695714 pathogenic Glutaric aciduria, type 1 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The GCDH c.1204C>T (p.Arg402Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 27/120918 control chromosomes at a frequency of 0.0002233, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant was found in multiple affected individuals with an established diagnosis of GA-I based on the clinical symptoms, characteristic findings on neuroimaging and quantitative analysis of organic acids in urine. Busquets (2000) and Zschocke (2000) report the frequency of the variant of interest in affected individuals as 22% and 25%, respectively. Functional studies using expression systems show the variant to have a complete loss of GCDH activity (Biery_1996, Keyser_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000002166 SCV000756248 pathogenic Glutaric aciduria, type 1 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 402 of the GCDH protein (p.Arg402Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs25762492, 121434369, ExAC 0.08%). This variant is the most common cause of glutaric acidemia I in Europe, although it has also been reported in other populations (PMID: 8900227, 10649503, 11073722, 20732827, 28438223, 28352331). ClinVar contains an entry for this variant (Variation ID: 2085). Experimental studies have shown that this missense change impairs the homo-oligomerization of GCDH protein and results in a loss of enzymatic activity (PMID: 8900227, 18775954) For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000002166 SCV000893504 pathogenic Glutaric aciduria, type 1 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000002166 SCV000923436 likely pathogenic Glutaric aciduria, type 1 2019-01-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002166 SCV001163800 pathogenic Glutaric aciduria, type 1 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002166 SCV001193812 likely pathogenic Glutaric aciduria, type 1 2019-12-04 criteria provided, single submitter clinical testing NM_000159.2(GCDH):c.1204C>T(R402W) is classified as likely pathogenic in the context of GCDH-related glutaric acidemia. Sources cited for classification include the following: PMID 8900227, 10699052, 24973495 and 18775954. Classification of NM_000159.2(GCDH):c.1204C>T(R402W) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255833 SCV001247983 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000002166 SCV001442996 pathogenic Glutaric aciduria, type 1 2020-06-01 criteria provided, single submitter clinical testing PS3, PS4_Supporting, PM2, PM3_Strong, PP4
Kasturba Medical College, Manipal University RCV000002166 SCV001478369 pathogenic Glutaric aciduria, type 1 2019-11-28 criteria provided, single submitter clinical testing
OMIM RCV000002166 SCV000022324 pathogenic Glutaric aciduria, type 1 2000-03-01 no assertion criteria provided literature only
GeneReviews RCV000002166 SCV001133282 pathogenic Glutaric aciduria, type 1 2019-09-12 no assertion criteria provided literature only Most common pan ethnic pathogenic variant

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