ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.1198G>A (p.Val400Met) (rs121434372)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224327 SCV000281622 pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000224327 SCV000329357 pathogenic not provided 2016-09-16 criteria provided, single submitter clinical testing The V400M missense change in the GCDH gene has been identified on 20% of alleles in Spanish patients with glutaric aciduria type I (GA1) (Christensen et al. 2004). Patients who are homozygous for V400M are reported to have 5%-15% residual glutaryl-CoA dehydrogenase activity (Christensen et al. 2004). The V400M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret V400M to be a pathogenic variant.
Invitae RCV000002169 SCV000756246 pathogenic Glutaric aciduria, type 1 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 400 of the GCDH protein (p.Val400Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs121434372, ExAC 0.02%). This variant has been reported as homozygous and in combination with another GCDH variant in individuals affected with glutaric acidemia type I (PMID: 27397597, 21912879, 10960496). ClinVar contains an entry for this variant (Variation ID: 2088). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000002169 SCV000893503 pathogenic Glutaric aciduria, type 1 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000002169 SCV000919422 pathogenic Glutaric aciduria, type 1 2017-10-26 criteria provided, single submitter clinical testing Variant summary: The GCDH c.1198G>A (p.Val400Met) variant involves the alteration of a conserved nucleotide that lies within the acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 28/277188 control chromosomes at a frequency of 0.000101, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). The variant has been identified in numerous glutaric acidemia I patients in homozygosity and compound heterozygosity (Busquets_2000; Christensen_2004). Studies on the residual GCDH enzyme activity levels in these patients show a range from almost no activity when in compound heterozygosity with a known null mutation (e.g., R402W), up to 30% of normal activity when in compound heterozygosity with a mild mutation (e.g., R227P). In homozygosity, the GCDH activity levels were 5-15% of WT ( Busquets_2000 and CHRISTENSEN_2004). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000002169 SCV001140998 pathogenic Glutaric aciduria, type 1 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000002169 SCV000022327 pathogenic Glutaric aciduria, type 1 2012-03-01 no assertion criteria provided literature only
Counsyl RCV000002169 SCV000678044 likely pathogenic Glutaric aciduria, type 1 2014-02-15 no assertion criteria provided clinical testing
GeneReviews RCV000002169 SCV001133277 pathogenic Glutaric aciduria, type 1 2019-09-12 no assertion criteria provided literature only common variant among low excreters in Spain

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