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

gnomAD frequency: 0.00014  dbSNP: rs121434372

Total submissions: 13

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	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 400 of the GCDH protein (p.Val400Met). This variant is present in population databases (rs121434372, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10960496, 21912879, 27397597). ClinVar contains an entry for this variant (Variation ID: 2088). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000002169	SCV000893503	pathogenic	Glutaric aciduria, type 1	2022-04-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Revvity Omics, Revvity	RCV000002169	SCV002024215	pathogenic	Glutaric aciduria, type 1	2023-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512671	SCV003752952	pathogenic	Inborn genetic diseases	2022-09-16	criteria provided, single submitter	clinical testing	The c.1198G>A (p.V400M) alteration is located in exon 11 (coding exon 10) of the GCDH gene. This alteration results from a G to A substitution at nucleotide position 1198, causing the valine (V) at amino acid position 400 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.011% (30/282716) total alleles studied. The highest observed frequency was 0.028% (2/7222) of Other alleles. This variant has been observed in the homozygous state and confirmed in trans with GCDH pathogenic variants in multiple individuals with clinical features of GCDH-related glutaricaciduria (Cerisola, 2009; Busquets, 2000; Marti-Masso, 2012; Biery, 1996; Del Rizzo, 2016; Schillaci, 2016; Kurkina, 2020; Martin-Rivada, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies show reduced enzyme activity in patient-derived fibroblasts or leukocytes (Christensen, 2004). Additionally, functional studies show reduced stability and ligand binding compared to controls in vitro (Ribeiro, 2020a; Ribeiro, 2020b). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000002169	SCV004199197	pathogenic	Glutaric aciduria, type 1	2023-09-28	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	not provided	Glutaric aciduria, type 1		no assertion provided	literature only	common variant among low excreters in Spain
Natera, Inc.	RCV000002169	SCV001456397	pathogenic	Glutaric aciduria, type 1	2020-09-16	no assertion criteria provided	clinical testing