Submissions for variant NM_000159.4(GCDH):c.1168G>C (p.Gly390Arg)

gnomAD frequency: 0.00006  dbSNP: rs372983141

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000429838	SCV000225201	pathogenic	not provided	2018-08-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000429838	SCV000521170	likely pathogenic	not provided	2022-11-26	criteria provided, single submitter	clinical testing	Identified in individuals suspected of GA 1 who also harbored a second GCDH variant, but it is not known whether the variants occurred on opposite alleles (in trans) (Christensen et al., 2004; Boneh et al., 2008; Barvinska et al., 2018; Kurkina et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9711871, 17188916, 8900228, 18411069, 32778825, 15505393, 32240488, 10960496)
Invitae	RCV000173983	SCV001234405	pathogenic	Glutaric aciduria, type 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the GCDH protein (p.Gly390Arg). This variant is present in population databases (rs372983141, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of glutaric acidemia type I (PMID: 8900228, 9711871, 15505393, 17188916; Invitae). ClinVar contains an entry for this variant (Variation ID: 193799). 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%. This variant disrupts the p.Gly390 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been observed in individuals with GCDH-related conditions (PMID: 9711871, 11073722, 27672653, 30298489), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000173983	SCV002018414	likely pathogenic	Glutaric aciduria, type 1	2020-10-11	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000173983	SCV003920008	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 (GA1) in both the homozygous and compound heterozygous states (Anikster 1996 PMID: 8900228; Christensen 2003 PMID: 15505393; Korman 2007 PMID: 17188916; Boneh 2008 PMID: 18411069; Adhikari 2020 PMID: 32778825; Kurkina 2020 PMID: 32240488). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.007% [5/68020], https://gnomad.broadinstitute.org/variant/19-12897788-G-C?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 also present in ClinVar, with several laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 193799). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, this variant is located in the FAD-binding domain of the encoded protein (Busquets 2000 PMID: 11073722), and several other variants at this position have been reported in individuals with GA1 (p.Gly390Ala, p.Gly390Glu, p.Gly390Trp, p.Gly390Val), further suggesting that this amino acid residue may have functional importance. In summary, this variant is classified as pathogenic based on the data above.
Baylor Genetics	RCV000173983	SCV004198747	pathogenic	Glutaric aciduria, type 1	2023-10-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173983	SCV004241652	pathogenic	Glutaric aciduria, type 1	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1168G>C (p.Gly390Arg) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251448 control chromosomes (gnomAD). c.1168G>C has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (examples: Anikster_1996, Christensen_2004, Korman_2007, Kurkina_2020). Different variants affecting this residue (ex: c.1168G>A (p.Gly390Arg), c.1169G>C (p.Gly390Ala)) have been classified pathogenic/likely pathogenic in ClinVar (CV ID 1070251, 371251). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8900228, 15505393, 17188916, 32240488). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000173983	SCV000800582	likely pathogenic	Glutaric aciduria, type 1	2019-03-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000173983	SCV001456396	pathogenic	Glutaric aciduria, type 1	2020-09-16	no assertion criteria provided	clinical testing