Submissions for variant NM_001360016.2(G6PD):c.148C>T (p.Pro50Ser)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Dunham Lab, University of Washington	RCV002305814	SCV002599162	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in two unrelated hemizygotes with G6PD deficiency (PS4_M, PP4). Decreased activity in red blood cells of hemizygote (20%) (PS3). Not observed in gnomAD (PM2). Post_P 0.989 (odds of pathogenicity 729.3, Prior_P 0.1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331343	SCV004037864	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.238C>T (p.Pro80Ser), also referred to as c.148C>T (p.Pro50Ser) and G6PD Kambos, results in a non-conservative amino acid change located in the NAD-binding domain (IPR022674) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183351 control chromosomes (gnomAD). c.238C>T has been reported in the literature in the hemizygous state in two individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (Drousiotou_2004). Whole blood enzyme activity from these individuals indicated that the variant activity was approximately 20% of normal (Drousiotou_2004), however, this has yet to be tested in a controlled functional study. These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 15223006). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical/functional evidence is available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002305814	SCV004299721	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-09-21	criteria provided, single submitter	clinical testing	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. 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. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 50 of the G6PD protein (p.Pro50Ser). ClinVar contains an entry for this variant (Variation ID: 1722704). This variant is also known as G6PD Kambos. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 15223006). This variant is not present in population databases (gnomAD no frequency).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596536	SCV005089784	likely pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing