ClinVar Genomic variation as it relates to human health

The missense variant p.R387C in G6PD (NM_001042351.3) has been previously reported in individuals affected with Chronic nonspherocytic hemolytic anemia (Keller et al, 2015). Experimental study depicts that the c.1159C >T mutation in the G6PD gene, results in a large reduction of G6PD enzyme activity ie; 14% (Vaca et al, 1982). The p.R387C variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R387C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 387 of G6PD is conserved in all mammalian species. The nucleotide c.1159 in G6PD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic

Variant found in unrelated hemizygotes with deficiency and CNSHA (PS4_M, PP4). In one family, hemizygote inherited from heterozygous mother (PP1); in another, variant is found in heterozygote but not in either parent so assumed de novo (PM6). Decreased activity in red blood cells (1-14%) and no detectable activity when expressed in E. coli (PS3). Affects same amino acid as pathogenic 387R>C (ClinVar ID 10396) (PM5). Within dimer interface (PM1). Predicted to be damaging or deleterious by multiple computational algorithms (PP3). Not found in gnomAD (PM2). Post_P 0.99996 (odds of pathogenicity 256136, Prior_P 0.1).

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 G6PD protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg387 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2602358, 12187030, 29248304; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10396). This missense change has been observed in individuals with G6PD deficiency (PMID: 1611091). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 387 of the G6PD protein (p.Arg387Cys).