Submissions for variant NM_000402.4(G6PD):c.934G>C (p.Asp312His)

gnomAD frequency: 0.00072  dbSNP: rs137852318

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000757322	SCV000232594	pathogenic	not provided	2013-11-12	criteria provided, single submitter	clinical testing
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000180200	SCV000236504	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2014-04-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180200	SCV000647803	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 282 of the G6PD protein (p.Asp282His). This variant is present in population databases (rs137852318, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with G6PD deficiency (PMID: 2912069, 5305539, 7806085, 7947239, 7947250, 8807321). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10372). 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%. Experimental studies have shown that this missense change affects G6PD function (PMID: 7806085, 7947239). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757322	SCV000885497	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing	The G6PD c.844G>C; p.Asp282His variant (rs137852318), also known as G6PD Seattle/Ferrara II/Modena/Athens-like, has been reported in multiple individuals in the Mediterranean region with G6PD deficiency (Cappellini 1994, Cappellini 1995, De Vita 1989, Frigerio 1994, Lenzerini 1969, Rattazzi 1969). Functional characterization indicates enzymatic activity ranging from 15 to 25 percent of wildtype (Cappellini 1994, Cappellini 1995, De Vita 1989, Frigerio 1994, Lenzerini 1969, Rattazzi 1969), consistent with a class III variant (WHO working group 1989). The variant is listed as pathogenic in ClinVar (Variation ID: 10372), and observed in the general population databases at a frequency of 0.07% (143/200329 alleles, including 52 hemizygotes) in the Genome Aggregation Database. The aspartate at codon 282 is moderately conserved, and computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the available information, this variant is classified as pathogenic. REFERENCES Cappellini M et al. Biochemical and molecular characterization of a new sporadic glucose-6-phosphate dehydrogenase variant described in Italy: G6PD Modena. Br J Haematol. 1994; 87(1):209-11. Cappellini M et al. Molecular characterisation of the glucose-6-phosphate dehydrogenase (G6PD) Ferrara II variant. Hum Genet. 1995; 95(4):440-2. De Vita G et al. Two point mutations are responsible for G6PD polymorphism in Sardinia. Am J Hum Genet. 1989; 44(2):233-40. Frigerio R et al. Molecular and biochemical data on some glucose-6-phosphate dehydrogenase variants from southern Sardinia. Haematologica. 1994; 79(4):319-21. Lenzerin L et al. Characterization of glucose-6-phosphate dehydrogenase variants. I. Occurrence of a G6PD Seattle-like variant in Sardinia and its interaction with the G6PD Mediterranean variant. Am J Hum Genet. 1969; 21(2):142-53. Rattazzi M et al. Characterization of glucose-6-phosphate dehydrogenase variants. II. G6PD Kephalonia, G6PD Attica, and G6PD Seattle-like" found in Greece. Am J Hum Genet. 1969; 21(2):154-67. WHO working group. Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 1989; 67(6):601-11. "
Fulgent Genetics, Fulgent Genetics	RCV000763204	SCV000893823	pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000180200	SCV001443774	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	This variant in exon 8 of the G6PD gene results in the amino acid substitution from Aspartic acid to Histidine at codon 312 (p.Asp312His) with the sequence change of c.934G>C (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<3.8 U/dL) which was screened for advanced newborn screening with confirmatory genetic reflex testing at lifecell diagnostics. The observed variant has a minor allele frequency of 0.0007040% in gnomAD database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. This is a Class III: variant associated with mild to moderate G6PD deficiency (0.10-0.60 normal activity), with intermittent hemolysis. The G6PD c.934G>C; p.Asp312His variant also referred to as c.844G>C; p.Asp282His, commonly known as G6PD-Ferrara II or Lodi or Modena or Seattle in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficieny by (Cappellini MD et al., 1994, PMID: 7947250; Alfinito F et al., 1994, PMID: 7947239; Rudilla F et al., 2019, PMID: 31681265)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000757322	SCV001446885	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000757322	SCV001715686	pathogenic	not provided	2020-12-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000757322	SCV001747681	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	G6PD: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting
GeneDx	RCV000757322	SCV001983798	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant reduces enzyme activity to 20% of wild type enzyme, and is associated with a mild form of G6PD deficiency (De Vita et al., 1989); This variant is associated with the following publications: (PMID: 2912069, 26990548, 30096395, 31681265, 7806085, 7947250, 8807321, 5305539, 7947239, 5770172, 4974311, 9299858, 34426522, 28902532, 35725860)
Mendelics	RCV000180200	SCV002516414	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000180200	SCV002587049	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2021-06-20	criteria provided, single submitter	research
Dunham Lab, University of Washington	RCV000180200	SCV002599347	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-08-12	criteria provided, single submitter	curation	Variant found in unrelated hemizygotes with deficiency, some with anemia, favism, and jaundice (PS4_M, PP4). In one family, hemizygous brothers have deficiency and heterozygous mother has decreased G6PD activity (PP1). Decreased activity in red blood cells (3-45%) and when expressed in E. coli (PS3). Predicted to be damaging by SIFT, probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.999 (odds of pathogenicity 6563, Prior_P 0.1).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000180200	SCV002768052	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-07-16	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 deficiency (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 aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (89 heterozygotes, 0 homozygotes, 53 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated G6PD C-terminal domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-known pathogenic allele also known as G6PD Seattle/Ferrara II/Modena/Athens-like (ClinVar, PMID: 11146567, 12064920, 25536053). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Enzyme activity in patient cells is reduced relative to wild type, and in vitro studies support abnormal protein function (PMID: 11146567, 12064920, 30096395). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I)
Baylor Genetics	RCV003466847	SCV004195379	pathogenic	Malaria, susceptibility to	2024-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001166655	SCV004222743	pathogenic	G6PD deficiency	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.934G>C (p.Asp312His) results in a non-conservative amino acid change located in the C-terminal 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 allele was found at a frequency of 0.0007 in 183239 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in G6PD causing Glucose 6 Phosphate Dehydrogenase Deficiency (0.29), allowing no conclusion about variant significance. The variant, c.934G>C (aka. c.844G>C (p.D282H), G6PD Seattle-like, Ferrara II, Modena, Athens-like and Lodi), has been reported in the literature in numerous individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency (e.g. DeVita_1989, Frigerio_1994, Alfinito_1994, diMontemuros_1997), including at least one case of an affected (hemizygous) male and heterozygous mother with decreased enzyme activity. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, and demonstrated decreased enzyme activity in hemizygous samples (~20 % of normal) as well as in in vitro expression systems (e.g. DeVita_1989, Frigerio_1994, Cappellini_1994, Cortes-Morales_2018, Alfinito_1994). The following publications have been ascertained in the context of this evaluation (PMID: 7806085, 30096395, 2912069, 7947250, 7947239, 9299858). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000757322	SCV005197993	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing
OMIM	RCV000011092	SCV000031319	other	G6PD SEATTLE-LIKE	2017-05-24	no assertion criteria provided	literature only
OMIM	RCV000011093	SCV000031320	other	G6PD MODENA	2017-05-24	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003904827	SCV004730016	pathogenic	G6PD-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The G6PD c.844G>C variant is predicted to result in the amino acid substitution p.Asp282His. This variant also described using legacy nomenclature as p.Asp312His, referred to as G6PD Seattle-like, has been reported in individuals with moderate glucose-6-phosphate dehydrogenase deficiency (see, for example, De Vita et al. 1989. PubMed ID: 2912069; Calabrò et al. 1993. PubMed ID: 8447319; Manco et al. 2023. PubMed ID: 36150187). In vitro experimental studies suggest this variant impacts protein function (Cappellini et al. 1995. PubMed ID: 7705842; Rodrigues et al. 2002. PubMed ID: 12064920; Cortés-Morales et al. 2018. PubMed ID: 30096395). An alternative nucleotide substitution affecting the same amino acid (p.Asp282Tyr) has also been reported in individuals with glucose-6-phosphate dehydrogenase deficiency (Kawamoto et al. 2006. PubMed ID: 16927025). This variant is reported in 0.11% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.