Submissions for variant NM_000159.4(GCDH):c.1213A>G (p.Met405Val)

gnomAD frequency: 0.00018  dbSNP: rs141437721

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414299	SCV000225199	pathogenic	not provided	2015-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000414299	SCV000490533	likely pathogenic	not provided	2025-03-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 16183314, 27397597, 25255367, 17188916, 28389991, 36976725, 28438223, 25590979, 36906724, 34207159, 34258142, 38296580, 37020324)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000173982	SCV001150116	pathogenic	Glutaric aciduria, type 1	2018-07-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000173982	SCV001193888	pathogenic	Glutaric aciduria, type 1	2021-11-08	criteria provided, single submitter	clinical testing	NM_000159.2(GCDH):c.1213A>G(M405V) is a missense variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. M405V has been observed in cases with relevant disease (PMID: 25590979, 19433275, 17188916, 27397597). Functional assessments of this variant are not available in the literature. M405V has been observed in population frequency databases (gnomAD: AFR 0.06%). In summary, NM_000159.2(GCDH):c.1213A>G(M405V) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173982	SCV001205420	pathogenic	Glutaric aciduria, type 1	2024-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 405 of the GCDH protein (p.Met405Val). This variant is present in population databases (rs141437721, gnomAD 0.05%). This missense change has been observed in individual(s) with glutaric acidemia, type I (PMID: 17188916, 27397597, 28438223). ClinVar contains an entry for this variant (Variation ID: 193798). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173982	SCV001360429	pathogenic	Glutaric aciduria, type 1	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1213A>G (p.Met405Val) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251442 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (6e-05 vs 0.0035), allowing no conclusion about variant significance. c.1213A>G has been reported in the literature (in compound heterozygous and homozygous state) in multiple individuals affected with Glutaric Acidemia Type 1 (GA-I) (e.g. Boy_2017, Cerisola_2009, Gallagher_2005, Korman_2007, Schillaci_2016). These data indicate that the variant is very likely to be associated with disease. These reports also indicated that this variant is associated with a low excretor biochemical phenotype, and therefore could potentially be missed by current new born screening programs that are using biochemical diagnosis based on elevated metabolites in the urine or blood (Schillaci_2016). The following publications have been ascertained in the context of this evaluation (PMID: 28438223, 19433275, 19167251, 16183314, 17188916, 27397597). Six 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.
Baylor Genetics	RCV000173982	SCV004191000	likely pathogenic	Glutaric aciduria, type 1	2024-03-19	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000173982	SCV004810261	pathogenic	Glutaric aciduria, type 1	2024-04-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000173982	SCV005655077	pathogenic	Glutaric aciduria, type 1	2023-12-28	criteria provided, single submitter	clinical testing
3billion	RCV000173982	SCV005903843	pathogenic	Glutaric aciduria, type 1	2023-10-24	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.87 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000193798 /PMID: 17188916). The variant is in trans with the other variant. A different missense change at the same codon (p.Met405Thr) has been reported to be associated with GCDH related disorder (ClinVar ID: VCV001995265). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews	RCV000173982	SCV001133278	not provided	Glutaric aciduria, type 1		no assertion provided	literature only	common variant among low-excreter African Americans
Natera, Inc.	RCV000173982	SCV002086999	pathogenic	Glutaric aciduria, type 1	2021-06-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955020	SCV004772990	pathogenic	GCDH-related disorder	2023-11-08	no assertion criteria provided	clinical testing	The GCDH c.1213A>G variant is predicted to result in the amino acid substitution p.Met405Val. This variant has been reported along with a second GCDH variant in patients with clinical and/or biochemical features of glutaric acidemia type I (for example, see Korman et al. 2007. PubMed ID: 17188916; Schillaci et al. 2016. PubMed ID: 27397597; Boy et al. 2017. PubMed ID: 28438223; Guenzal et al. 2021. PubMed ID: 34258142). It has been reported in association with reduced GCDH enzyme activity and low excretion of glutaric acid. Importantly, low-excretor patients may be more difficult to detect with biochemical testing as well as in newborn screening based on C5DC acylcarnitine (Schillaci et al. 2016. PubMed ID: 27397597; Larson et al. 2019. PubMed ID: 31536184). This variant is reported in 0.064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008647-A-G). This variant is interpreted as pathogenic.