Submissions for variant NM_000159.4(GCDH):c.281G>A (p.Arg94Gln)

dbSNP: rs566417795

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485466	SCV000565028	likely pathogenic	not provided	2016-08-26	criteria provided, single submitter	clinical testing	The R94Q (c.281 G>A) variant in the GCDH gene has previously been reported in two siblings believed to have glutaric aciduria type I (GA1) who were low glutaric acid excretors and were compound heterozygous for R94Q (c.281 G>A) and another missense variant in the GCDH gene (Gupta et al. 2015). The R94Q (c.281 G>A) variant has also been seen at GeneDx in a patient sent for analysis of the GCDH gene after abnormal newborn screening results who also harbored the R402W pathogenic variant on the opposite GCDH allele (in trans). The R94Q (c.281 G>A) variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R94Q variant is a semi-conservative amino acid substitution, which occurs at a position that is highly conserved. In silico analysis predicts that R94Q is probably damaging to the protein structure/function. Furthermore, several in-silico splice prediction models predict that the c.281 G>A nucleotide substitution, responsible for R94Q, creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, we interpret R94Q (c.281 G>A) to be likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675080	SCV000964927	pathogenic	Glutaric aciduria, type 1	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the GCDH protein (p.Arg94Gln). This variant is present in population databases (rs566417795, gnomAD 0.1%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 25762492; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418224). 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%. Experimental studies have shown that this missense change affects GCDH function (PMID: 11024031). This variant disrupts the p.Arg94 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600243). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000675080	SCV001478370	pathogenic	Glutaric aciduria, type 1	2019-11-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000675080	SCV002768946	pathogenic	Glutaric aciduria, type 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria type I (GA-I, MIM#231670). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (31 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. The alternative amino acid change to leucine, p.(Arg94Leu) has been reported as likely pathogenic (3x) in ClinVar, however, it has not been used as supporting evidence as the change to leucine has a much larger Grantham score. In addition, p.(Arg94Trp) has been reported as a VUS in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in 8 individuals, including three unrelated families with GA-I (low excreter biochemical phenotype) in both compound heterozygous and homozygous state (ClinVar, PMIDs: 25762492, 31302874, 33728242, 33138774) (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Experimental studies have shown a significantly reduced Kcat of GCDH to 2% to 3% of wild type GCDH (PMID: 11024031). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000675080	SCV002811884	likely pathogenic	Glutaric aciduria, type 1	2022-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000675080	SCV003832943	likely pathogenic	Glutaric aciduria, type 1	2022-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000675080	SCV003922545	pathogenic	Glutaric aciduria, type 1	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.281G>A (p.Arg94Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 0.00012 in 251464 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.281G>A has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Gupta_2015, Foran_2021, Healy_2022), including two siblings. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function indicating about 2% residual activity with glutaryl- CoA as substrate (Dwyer_2001). Another variant affecting the same amino acid (c.281G>T, p.Arg94Leu) has also been associated with GA1, suggesting an important role for this amino acid. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as pathogenic (n=3), likely pathogenic (n= 4) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000675080	SCV004048470	pathogenic	Glutaric aciduria, type 1		criteria provided, single submitter	clinical testing	The missense variant c.281G>A (p.Arg94Gln) in GCDH gene has been observed in combination with another GCDH variant in individual(s) with glutaric acidemia (Gupta N et.al.,2015). This variant has been reported to affect GCDH protein function (Dwyer TM et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg94Gln variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01233% is reported in gnomAD. The amino acid Arg at position 94 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg94Gln in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000675080	SCV004198749	likely pathogenic	Glutaric aciduria, type 1	2024-03-26	criteria provided, single submitter	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000675080	SCV005873675	pathogenic	Glutaric aciduria, type 1	2020-11-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000675080	SCV000800580	uncertain significance	Glutaric aciduria, type 1	2017-08-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000675080	SCV001454368	likely pathogenic	Glutaric aciduria, type 1	2020-09-16	no assertion criteria provided	clinical testing