Submissions for variant NM_001360016.2(G6PD):c.835A>T (p.Thr279Ser)

dbSNP: rs2148329890

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV001781140	SCV002025182	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-04-19	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV001781140	SCV002599238	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in hemizygotes with G6PD deficiency (PP4). Decreased activity in red blood cells (20-40%) (PS3). Not found in gnomAD (PM2). Post_P 0.949 (odds of pathogenicity 168.4, Prior_P 0.1).
Baylor Genetics	RCV003470911	SCV004195402	likely pathogenic	Malaria, susceptibility to	2023-05-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001781140	SCV004299711	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 279 of the G6PD protein (p.Thr279Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with G6PD deficiency (PMID: 1459579, 20203002, 27495838). This variant is also known as Chinese-1. ClinVar contains an entry for this variant (Variation ID: 1324435). 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 with a positive predictive value of 80%. This variant disrupts the p.Thr279 amino acid residue in G6PD. Other variant(s) that disrupt this residue have been observed in individuals with G6PD-related conditions (PMID: 11295127, 27495838), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001781140	SCV005086927	uncertain significance	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient haemolytic anaemia (favism) (MIM#300908). (I) 0109 - This gene is associated with X-linked recessive disease. Hemizygous males and homozygous females are commonly affected, however some heterozygous female carriers can also be affected depending on X inactivation. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to serine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated G6PD_C domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A change to alanine has been reported in an individual with G6PD deficiency, however it is unclear whether they presented with anemia (PMID: 11295127). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic in ClinVar and detected in individuals with reduced G6PD enzyme activity levels in Chinese newborn screening and anemia screening (PMIDs: 36212142, 27495838, 1459579, 11295127), however it is unclear whether they presented with anemia. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Enzyme activity and or G6PD/6PGD ratio was reduced in individuals going through newborn or anemia screening (PMIDs: 36212142, 27495838, 1459579, 11295127). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699470	SCV005203880	pathogenic	G6PD deficiency	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.925A>T (p.Thr309Ser) results in a conservative amino acid change located in the glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183272 control chromosomes. c.925A>T has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. Beutler_1992, Gao_2020, Xia_2016, Yan_2010). These data indicate that the variant is very likely to be associated with disease. This variant is also known as c.835A>T(p.T279S) and Chinese-1. The following publications have been ascertained in the context of this evaluation (PMID: 1459579, 34134107, 27495838, 20203002). ClinVar contains an entry for this variant (Variation ID: 1324435). Based on the evidence outlined above, the variant was classified as pathogenic.