Submissions for variant NM_000402.4(G6PD):c.1147C>T (p.Pro383Ser)

dbSNP: rs137852333

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Dunham Lab, University of Washington	RCV002305433	SCV002599356	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency (PS4_M, PP4). Decreased activity in red blood cells (0-5%) (PS3). Predicted to be damaging by SIFT, and probably damaging by PolyPhen (PP3). Not found in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
Invitae	RCV002305433	SCV003445964	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-04-27	criteria provided, single submitter	clinical testing	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: 10385). This variant is also known as G6PD Ierapetra. This missense change has been observed in individual(s) with glucose-6-phosphate dehydrogenase deficiency (PMID: 1611091, 10782016). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 353 of the G6PD protein (p.Pro353Ser). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323355	SCV004028678	pathogenic	G6PD deficiency	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.1147C>T (p.Pro383Ser) results in a non-conservative amino acid change located in the C-terminal Glucose-6-phosphate dehydrogenase domain (IPR022675) 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 170326 control chromosomes in gnomAD. c.1147C>T, also described as G6PD Ierapetra, has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (example: Menounos_2000, Xu_1995). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity of G6PD (example: Beutler_1992). The following publications have been ascertained in the context of this evaluation (PMID: 1611091, 10782016, 7803800). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic: n=2; Other per OMIM). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011115	SCV000031342	other	G6PD IERAPETRA	2017-05-24	no assertion criteria provided	literature only