Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169460 | SCV000220886 | likely pathogenic | Glutaric aciduria, type 1 | 2014-11-14 | criteria provided, single submitter | literature only | |
| Fulgent Genetics, |
RCV000169460 | SCV000894183 | likely pathogenic | Glutaric aciduria, type 1 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000169460 | SCV000960222 | pathogenic | Glutaric aciduria, type 1 | 2023-12-19 | 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 128 of the GCDH protein (p.Arg128Gln). This variant is present in population databases (rs755586631, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 10699052, 15505393, 19433437, 21176883, 28438223). ClinVar contains an entry for this variant (Variation ID: 189063). 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. |
| Revvity Omics, |
RCV000169460 | SCV002018412 | likely pathogenic | Glutaric aciduria, type 1 | 2021-10-07 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169460 | SCV002511409 | pathogenic | Glutaric aciduria, type 1 | 2022-04-08 | criteria provided, single submitter | clinical testing | Variant summary: GCDH c.383G>A (p.Arg128Gln) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251442 control chromosomes (gnomAD). c.383G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1, including at least 3 homozygotes (Zschocke_2000, Boy_2017, Tamhankar_2020) and several compound heterozygotes (e.g. Zschocke_2000, Mushimoto_2011, Boy_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: two have classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000169460 | SCV002767874 | pathogenic | Glutaric aciduria, type 1 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glutaricaciduria, type I (MIM#231670). Dominant-negative has also been suggested as a mechanism for this gene, however, there is currently limited evidence demonstrating this (GeneReviews). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). 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 (6 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Acyl-CoA dehydrogenase, N-terminal domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg128Gly) variant has informative conservation and has been previously been reported as a pathogenic variant (PMID: 9711871). (N) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with glutaricaciduria, type I (MIM#231670) (PMIDs: 18459892; 10699052; 21176883; 31062211; 32508882) (SP). 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Baylor Genetics | RCV000169460 | SCV004190998 | pathogenic | Glutaric aciduria, type 1 | 2023-10-14 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000169460 | SCV001454369 | pathogenic | Glutaric aciduria, type 1 | 2020-09-16 | no assertion criteria provided | clinical testing |