Submissions for variant NM_001360016.2(G6PD):c.595A>G (p.Ile199Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Dunham Lab, University of Washington	RCV002305809	SCV002599411	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-09-01	criteria provided, single submitter	curation	Reported in a heterozygote with 25% normal G6PD activity, and in two individuals (at least 1 hemizygote) with G6PD deficiency (PP4). Reduced activity in functional assay (PS3). Predicted to have decreased function (PP3). Located in substrate binding site (PM1) and very low frequency in gnomAD (PM2).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002305809	SCV004299713	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 199 of the G6PD protein (p.Ile199Val). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on G6PD function (PMID: 16193512). 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. ClinVar contains an entry for this variant (Variation ID: 1722699). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 18056001, 25536053). This variant is present in population databases (rs781865768, gnomAD 0.01%).