ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect; specifically, expression studies in E.coli found the activity of the A382T mutant protein to be 0.2% of normal activity (Goodman et al., 1998); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified in patients with glutaric acidemia, however zygosity and additional phenotypic information was not reported (Goodman et al., 1998; Alfadhel et al., 2016); This variant is associated with the following publications: (PMID: 9711871, 27629047)

Variant summary: GCDH c.1144G>A (p.Ala382Thr) 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 4e-06 in 251450 control chromosomes (gnomAD). c.1144G>A has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1 (Goodman_1998, Alfadhel_2016, E_2021, Sitta_2021, Martin-Rivada_2022). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant significantly decreases enzyme activity when expressed in E. coli (Goodman_1998). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

The GCDH c.1144G>A variant is predicted to result in the amino acid substitution p.Ala382Thr. This variant has been reported in individuals with glutaric acidemia 1 (Goodman et al. 1998. PubMed ID: 9711871; Alfadhel et al. 2016. PubMed ID: 27629047; Martín-Rivada et al. 2022. PubMed ID: 35281663). Experimental studies suggest this variant impacts protein function (Goodman et al. 1998. PubMed ID: 9711871). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13008578-G-A). Taken together, this variant is interpreted as likely pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 382 of the GCDH protein (p.Ala382Thr). This variant is present in population databases (rs567564095, gnomAD 0.008%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 27629047, 33064266). ClinVar contains an entry for this variant (Variation ID: 286241). 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: 9711871). For these reasons, this variant has been classified as Pathogenic.