ClinVar Miner

Submissions for variant NM_000159.3(GCDH):c.1204C>T (p.Arg402Trp) (rs121434369)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000002166 SCV000485128 likely pathogenic Glutaric aciduria, type 1 2016-03-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255833 SCV000225200 pathogenic not provided 2015-04-20 criteria provided, single submitter clinical testing
Fulgent Genetics RCV000002166 SCV000893504 pathogenic Glutaric aciduria, type 1 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255833 SCV000321707 pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing The R402W variant in the GCDH gene has been reported previously in the homozygous and compound heterozyous states, opposite of another GCDH variant, in multiple individuals with biochemical profiles and clinical features consistent with glutaric acidemia type 1 (Biery et al.. 1996; Busquets et al., 2000; Georgiou et al., 2014; Gupta et al., 2015). The R402W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R402W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies in E.coli and BHK cells transfected with R402W mutant plamids demonstrated reduced glutaryl-CoA dehydrogenase (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). Missense variants in nearby residues (Y398C, V400M, H403Y, H403R, M405V, N406K, L407V, L407P) and a different substitution at the same codon (R402Q), have been reported in the Human Gene Mutation Database in association with glutaric acidemia type I (GA1) (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R402W as a pathogenic variant.
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
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.
Integrated Genetics/Laboratory Corporation of America 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 2018-05-24 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.
OMIM RCV000002166 SCV000022324 pathogenic Glutaric aciduria, type 1 2000-03-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.