Submissions for variant NM_000402.4(G6PD):c.185A>G (p.His62Arg)

gnomAD frequency: 0.00008  dbSNP: rs137852340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798781	SCV000938413	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 32 of the G6PD protein (p.His32Arg). This variant is present in population databases (rs137852340, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with G6PD deficiency (PMID: 10502785, 11601226, 16329560, 29339739, 30315739). It is commonly reported in individuals of Asian ancestry (PMID: 29339739). This variant is also known as G6PD Gaohe. ClinVar contains an entry for this variant (Variation ID: 10403). 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 95%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000798781	SCV001142117	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000798781	SCV002557570	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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). (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 histidine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes, 7 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This founder mutation in Asian population that is also known as G6PD Gaohe have been reported in multiple individuals with G6PD deficiency (ClinVar, PMID: 29339739, 33051526). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Dunham Lab, University of Washington	RCV000798781	SCV002599305	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in hemizygtes with G6PD deficiency, some with anemia and jaundice (PP4). Decreased activity in red blood cells of hemizygotes (0-38%) (PS3). Identified in unrelated individuals with G6PD deficiency (PS4_M). Modeling predicts disruption of function (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.994 (odds of pathogenicity 1517, Prior_P 0.1).
Fulgent Genetics, Fulgent Genetics	RCV002496323	SCV002809324	likely pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512966	SCV003611765	pathogenic	Inborn genetic diseases	2022-09-12	criteria provided, single submitter	clinical testing	The c.95A>G (p.H32R) alteration is located in exon 2 (coding exon 1) of the G6PD gene. This alteration results from an A to G substitution at nucleotide position 95, causing the histidine (H) at amino acid position 32 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.014% (29/204635) total alleles studied. The highest observed frequency was 0.196% (29/14827) of East Asian alleles. This variant accounts for more than 20% of pathogenic alleles in the Chinese population and has been detected alone or in conjunction with another G6PD variant in individuals with G6PD deficiency (Chiu, 1993; Zhong, 2018; Chen, 2018; Fu, 2018; Ohlsson, 2019; He, 2020; Wang, 2021; Xu, 2021; Pan, 2021; Xu, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV003460456	SCV004195391	pathogenic	Malaria, susceptibility to	2024-03-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000798781	SCV004235993	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525851	SCV005039937	pathogenic	G6PD deficiency	2024-03-08	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.185A>G (p.His62Arg) [NM_001035810.1:c.95A>G (p.His32Arg)], also referred to as G6PD Gaohe/Gaozhou/Sapporo-like/Ube/Bodia-like, results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 182995 control chromosomes predominantly in the East Asian population. This frequency is not significantly higher than estimated for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.00015 vs 0.29), allowing no conclusion about variant significance. c.185A>G has been reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and as a G6PD hotspot mutation in the Chinese population (example, Ainoon_1999, Fu_2018, Sun_2022). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal G6PD enzyme activity (Ainoon_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10502785, 29339739, 16607506, 36353116). ClinVar contains an entry for this variant (Variation ID: 10403). Based on the evidence outlined above, the variant was classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004540993	SCV005040797	pathogenic	Early-onset coronary artery disease	2024-03-08	criteria provided, single submitter	clinical testing
OMIM	RCV000011146	SCV000031373	other	G6PD GAOHE	2023-09-05	no assertion criteria provided	literature only