ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.682C>T (p.Arg228Cys)

gnomAD frequency: 0.00003  dbSNP: rs137852330
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000991015 SCV001142108 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2022-05-27 criteria provided, single submitter clinical testing
Lifecell International Pvt. Ltd RCV000991015 SCV001443092 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing This variant in exon 6 of the G6PD gene results in the amino acid substitution from Arginine to Cystine at codon 228 (p.Arg228Cys) with the sequence change of c.682C>T (NM_000402.4). This variant was observed in a proband with decreased level of G6PD enzyme (<2.4 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 0.0000327% 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 II variant associated with moderate G6PD deficiency (<10% activity), with intermittent hemolysis. The G6PD c.682C>T; p.Arg228Cys variant, also referred to as c.592C>T; p.Arg198Cys, commonly known as G6PD-Coimbra or Shunde or Vancouver in the literature. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (He Y et al., 2020 PMID: 33051526; Islam MT et al., 2018 PMID: 30097005; Lee J et al., 2018 PMID: 29548282)
Invitae RCV000991015 SCV001586055 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 198 of the G6PD protein (p.Arg198Cys). This variant is present in population databases (rs137852330, gnomAD 0.02%). This missense change has been observed in individual(s) with G6PD-related conditions (PMID: 1551674, 7789945, 11499668, 16155737, 16927025). This variant is also known as G6PD Coimbra. ClinVar contains an entry for this variant (Variation ID: 10391). 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: 8118045). For these reasons, this variant has been classified as Pathogenic.
Dunham Lab, University of Washington RCV000991015 SCV002599339 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 jaundice (PS4_M, PP4). Decreased activity in red blood cells (0-8%) (PS3). Located in substrate binding site (PM1). Affects same amino acid as pathogenic 198R>H (ClinVar ID 10417) and 198R>P (ClinVar ID 10394)(PM5). Predicted to be deleterious by in silico algorithms (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Not found in gnomAD (PM2). Post_P 0.9998 (odds of pathogenicity 59154, Prior_P 0.1).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000991015 SCV003921807 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2021-05-07 criteria provided, single submitter clinical testing 0102 - Loss of function is a known mechanism of disease in this gene and is associated with G6PD deficient hemolytic anemia (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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes, 3 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated NAD binding domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple individuals with G6PD deficiency and is often referred to as the Coimbra (592C>T) variant. It is commonly reported in hemizygous males, however a few affected heterozygous female carriers have also been identified (ClinVar, PMIDs: 1551674, 12497642, 33051526, 33628497). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Hemizygous males have been reported to have undetectable or severely reduced enzyme activity, classified as class II, whereas a small number of heterozygous females have been reported with moderate G6PD deficiency, classified as class III (PMIDs: 12497642, 22293322, 33051526). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000991015 SCV004171269 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency criteria provided, single submitter clinical testing The missense c.592C>T(p.Arg198Cys) variant in G6PD gene has been reported previously in individual(s) affected with G6PD-related conditions (Roca-Feltrer A, et. al., 2014; Nuchprayoon I, et. al., 2008). Experimental studies show that this variant affects G6PD function (Jiang W, et. al., 2006). The p.Arg198Cys variant has been reported with allele frequency of 0.003% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Arg198Cys in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 198 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003460454 SCV004195406 pathogenic Malaria, susceptibility to 2023-04-18 criteria provided, single submitter clinical testing
OMIM RCV000011126 SCV000031353 other G6PD COIMBRA 2017-05-24 no assertion criteria provided literature only

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