Submissions for variant NM_000159.4(GCDH):c.1240G>A (p.Glu414Lys)

gnomAD frequency: 0.00014  dbSNP: rs147611168

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790682	SCV000225202	pathogenic	not provided	2017-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173984	SCV000631932	pathogenic	Glutaric aciduria, type 1	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 414 of the GCDH protein (p.Glu414Lys). This variant is present in population databases (rs147611168, gnomAD 0.01%). This missense change has been observed in individual(s) with glutaric acidemia type I and has been described as a common cause of the disease in the Lumbee population (PMID: 8900227, 16466958, 19433437). It is commonly reported in individuals of Lumbee ancestry (PMID: 8900227, 16466958, 19433437). ClinVar contains an entry for this variant (Variation ID: 167133). 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: 18775954). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000173984	SCV002024225	pathogenic	Glutaric aciduria, type 1	2019-11-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000790682	SCV002064417	pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000790682	SCV002512910	pathogenic	not provided	2020-06-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that E414K had significantly reduced enzymatic activity when compared to wild-type (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: 16466958, 28438223, 29201125, 25087612, 18775954, 8900227, 29458885, 19433437, 32508882, 31589614)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000173984	SCV003920009	pathogenic	Glutaric aciduria, type 1	2022-06-21	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in several individuals with glutaric aciduria type 1 in both the homozygous and compound heterozygous states (Biery 1996 PMID: 8900227; Basinger 2006 PMID: 16466958; Keyser 2008 PMID: 18775954; Harting 2009 PMID: 19433437; Boy 2017 PMID: 28438223; Peng 2018 PMID: 29458885; Xiao 2020 PMID: 32508882). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.02% [11/41408], (https://gnomad.broadinstitute.org/variant/19-12897860-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID: 167133). Evolutionary conservation and computational predictive tools support that this variant will impact the protein. In vitro functional studies also support that this variant will impact the protein, resulting in no enzymatic activity (Biery 1996 PMID: 8900227; Keyser 2008 PMID: 18775954). In summary, this variant is classified as pathogenic based on the data above.
PreventionGenetics, part of Exact Sciences	RCV003398804	SCV004119974	pathogenic	GCDH-related disorder	2023-09-30	criteria provided, single submitter	clinical testing	The GCDH c.1240G>A variant is predicted to result in the amino acid substitution p.Glu414Lys. This variant has been reported in the heterozygous state with a second GCDH variant in patients with glutaric acidemia type I (GA1) (Harting et al. 2009. PubMed ID: 19433437; Boy et al. 2017. PubMed ID: 28438223). The c.1240G>A variant has also been reported as a common pathogenic variant in the Lumbee population of North Carolina (Basinger et al. 2006. PubMed ID: 16466958). Internally, we have observed this variant in the homozygous state or compound heterozygous with a second causative GCDH variant in several individuals with abnormal newborn screens and follow-up biochemical testing suggestive of GA1. In functional studies, the p.Glu414Lys substitution, as well as a p.Glu414Gln mutation of the same codon, has been reported to lead to greatly reduced to absent enzyme activity (Biery et al. 1996. PubMed ID: 8900227; Keyser et al. 2008. PubMed ID: 18775954). The p.Glu414 amino acid residue is located in the enzyme active site, and the p.Glu414Lys substitution was noted to interfere with ligand binding in functional assays (Keyser et al. 2008. PubMed ID: 18775954). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008674-G-A). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000173984	SCV004190994	pathogenic	Glutaric aciduria, type 1	2024-03-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173984	SCV004222936	pathogenic	Glutaric aciduria, type 1	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1240G>A (p.Glu414Lys) results in a conservative amino acid change located in the acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 250166 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (4.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.1240G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Glutaric Acidemia Type 1, including individuals of Lumbee heritage, a community in which it has been described as a founder variant (e.g. Basinger_2006, Boy_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (Keyser_2008) and found that variant effect results in <10% activity compared to the WT protein. The following publications have been ascertained in the context of this evaluation (PMID: 16466958, 28438223, 18775954). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000790682	SCV005330812	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	GCDH: PM1, PM2, PM3, PM5, PP4:Moderate, PP3, PS3:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000790682	SCV005413328	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_moderate, PM3, PS3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000173984	SCV005416213	pathogenic	Glutaric aciduria, type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP4+PP3_Strong
GeneReviews	RCV000173984	SCV001133283	not provided	Glutaric aciduria, type 1		no assertion provided	literature only	Founder variant in Lumbee Native Americans of North Carolina
Natera, Inc.	RCV000173984	SCV001456399	pathogenic	Glutaric aciduria, type 1	2020-09-16	no assertion criteria provided	clinical testing