ClinVar Genomic variation as it relates to human health

Variant summary: The GCDH c.877G>A (p.Ala293Thr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC and cohorts reported in the literature at a frequency of 0.0002717 (33/121474 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). In the literature, the variant has been identified in numerous patients with glutaric acidemia type 1 in a homozygous and compound heterozygous state (van der Watt_MGM_2010; Christensen_JIMD_2004). Each of these studies also performed GCDH enzyme activity assays, which showed that the variant is a functional null allele, resulting in undetectable or very low activity (van der Watt_MGM_2010; Christensen_JIMD_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The p.Ala293Thr variant in GCDH has been reported in at least 20 individuals with glutaric aciduria type 1, including eleven compound heterozygotes and five homozygotes, and segregated with disease in three affected individuals from three families (Biery 1996 PMID: 8900227, Ojwang 2001 PMID: 12199454, Mahfoud 2004 PMID: 15573311, Adhikari 2020 PMID: 32778825, Sitta 2021 PMID: 33064266, Busquets 2000 PMID: 10960496). It has also been identified in is 0.0290% (12/41462) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 2083). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function by eliminating glutaryl-CoA dehydrogenase activity (Busquets 2000 PMID:10960496); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive glutaryl-CoA dehydrogenase deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PP4, PP1_Strong, PS3_Moderate.

Across a selection of the available literature, the GCDH c.877G>A (p.Ala293Thr) variant has been identified in a homozygous state in 21 probands with glutaric acidemia and one asymptomatic individual, in a compound heterozygous state in 15 affected probands, and in a heterozygous state in 23 healthy individuals (Biery et al. 1996; Anikster et al. 1996; Busquets et al. 2000; Christensen et al. 2004; Van der Watt et al. 2010; Flamand-Rouviere et al. 2010). The p.Ala293Thr variant was absent from 50 controls but is reported at a frequency of 0.00058 in the African population of the Exome Aggregation Consortium. Functional studies performed in vivo using proband fibroblast or leukocyte cells demonstrated that the p.Ala293Thr variant resulted in zero to eleven percent of normal glutaryl-CoA dehydrogenase enzyme activity compared to controls, with homozygotes exhibiting less than one percent activity (Busquets et al. 2000; Christensen et al. 2004; Kolker et al. 2006; Flamand-Rouviere et al. 2010). Based on the collective evidence, the p.Ala293Thr variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting, PM3 strong, PP3 supporting

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 293 of the GCDH protein (p.Ala293Thr). This variant is present in population databases (rs121434371, gnomAD 0.04%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 8900227, 8900228, 10960496, 12199454, 15573311). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2083). 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: 8900227). For these reasons, this variant has been classified as Pathogenic.

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: 17188916, 8900228, 8900227, 31536184, 9711871, 28794906, 27397597, 28281424, 25087612, 20629163, 15505393, 15573311, 12199454, 32556492, 20732827, 19433437, 16641220, 10960496, 28062662, 29086383, 30570710, 26071121, 33064266, 32778825, 39211641, 38137040, 37685964, 36906724, 36913764, 38714461, 37020324)

PS3+PS4+PM3+PP3+PP4

Founder variant in South African Xhosa peoples

Variant classified as Pathogenic and reported on 05-09-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.