Submissions for variant NM_000402.4(G6PD):c.577G>A (p.Gly193Ser)

dbSNP: rs137852314

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657881	SCV000331249	pathogenic	not provided	2016-06-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507435	SCV000603774	pathogenic	not specified	2017-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV000282708	SCV000768478	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 163 of the G6PD protein (p.Gly163Ser). This variant is present in population databases (rs137852314, gnomAD 0.04%). This missense change has been observed in individuals with glucose-6-phosphate dehydrogenase deficiency (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). It is commonly reported in individuals of South Asian ancestry (PMID: 2503817, 11499668, 11793482, 21989994, 23926329, 26226515, 27880809). This variant is also known as G6PD Mahidol. ClinVar contains an entry for this variant (Variation ID: 10367). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects G6PD function (PMID: 8118045, 17959407, 22165289). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657881	SCV000779644	pathogenic	not provided	2023-06-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G163S is less stable than wild type in both thermostability and urea-induced inactivation tests, and is also impaired in its folding properties (Huang et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20007901, 22165289, 29548282, 33069889, 34272389, 31323480, 11793482, 12215013, 36212142, 34659341, 33637102, 21989994, 27880809, 2503817, 29240263, 28356147, 28138089, 11499668, 1924316, 8956035, 15349799, 4435794, 1562739, 31589614, 34953813, 30097005, 17959407, 29251006, 28376293)
Fulgent Genetics, Fulgent Genetics	RCV000763205	SCV000893825	pathogenic	Malaria, susceptibility to; Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000282708	SCV001164403	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2018-12-03	criteria provided, single submitter	research	The hemizygous p.Gly193Ser variant in G6PD was identified by our study in one individual with non-spherocytic hemolytic anemia due to G6PD deficiency. This variant has been identified in 0.03657% (7/19142) of South Asian chromosomes, including 3 hemizygous individuals, and 0.01442% (2/13869) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852314). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, most individuals with non-spherocytic hemolytic anemia due to G6PD deficiency are asymptomatic. This variant has been reported pathogenic in ClinVar (Variation ID: 10367). The p.Gly193Ser variant in G6PD has been reported in 75 Southeast Asian individuals with G6PD Deficiency in the literature (PMID: 27880809, 2503817, 11499668, 15349799). The prevalence of this variant in affected individuals is significantly increased compared to the prevalence in large population studies, supporting pathogenicity. In vitro functional studies provide some evidence that the p.Gly193Ser variant may impact protein stability, activity, (PMID: 17959407, 8118045). In summary, the p.Gly193Ser variant is pathogenic. ACMG/AMP Criteria applied: PP3, PS3, PS4 (Richards 2015).
Lifecell International Pvt. Ltd	RCV000282708	SCV001443095	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 Glycine to Serine at codon 193 (p.Gly193Ser) with the sequence change of c.577G>A (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 0.00004400% 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.577G>A; p.Gly193Ser variant, also referred to as c.487G>A; p.Gly163Ser. This variant has previously been reported for Glucose-6- phosphate dehydrogenase (G6PD) deficiency by (Sarker SK et al., 2016 PMID: 27880809; Li Q et al., 2015 PMID: 26226515; Narang A et al., 2020 PMID: 32906206.)
Revvity Omics, Revvity	RCV000282708	SCV002023785	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-10-30	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000282708	SCV002059872	likely pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2017-04-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000282708	SCV002516419	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298440	SCV002598619	pathogenic	G6PD deficiency	2022-09-08	criteria provided, single submitter	clinical testing	Variant summary: G6PD c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Glucose-6-phosphate dehydrogenase, NAD-binding domain (IPR022674) 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 4.4e-05 in 181825 control chromosomes. c.577G>A, also known as G6PD Mahidol has been widely reported in the literature in multiple individuals affected with Glucose 6 Phosphate Dehydrogenase Deficiency and is considered among one of the most frequent mutations described among individuals of Vietnamese ancestry (example, Bancone_2019). These data indicate that the variant is very likely to be associated with disease. Mahidol variant has been shown to cause low or very low enzymatic activity in RBCs and is associated with relatively high hemolytic risk by 8-aminoquinolines treatment (cited in Bancone_2019). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Dunham Lab, University of Washington	RCV000282708	SCV002599331	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, favism, and anemia (PS4_M, PP4). Decreased activity in red blood cells (0-30%) (PS3). Predicted to be damaging by SIFT and PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Reported as pathogenic by multiple clinical testing groups (PP5). Post_P 0.997 (odds of pathogenicity 3155, Prior_P 0.1).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000282708	SCV003921875	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2019-08-29	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 haemolytic anemia (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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 for a recessive condition (5 heterozygotes, 3 hemizygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated NAD binding domain (Pfam). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change to aspartic acid has been described in individuals with severe G6PD deficiency (WHO class I; PMID: 27880809). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common pathogenic G6PD variants in Thai and Burmese populations (WHO class II or III; ClinVar, PMID: 22171972, PMID: 25536053) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant results in impaired folding and reduced protein stability (PMID: 17959407). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genetics and Molecular Pathology, SA Pathology	RCV000282708	SCV004175317	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2023-02-07	criteria provided, single submitter	clinical testing	The G6PD c.487G>A variant is classified as Pathogenic (PS3_Moderate, PS4, PM1, PM5, PP3) The G6PD c.487G>A variant is located in a splice region. The G6PD c.487G>A variant is a single nucleotide change in exon 6/13 of the G6PD gene, which is predicted to change the amino acid glycine at position 163 in the protein to serine. The variant is commonly reported in patients with a clinical presentation of Glucose-6-phosphate dehydrogenase deficiency and haemolytic anaemia (HGMD:CM890050) (PS4). A molecular modelling of G6PD(p.Gly163Ser) was performed based on the X-ray structure of human G6PD. It is suggested that Ser-163 might affect the stability of G6PD alpha-helix d and beta-strand E, besides the conformation of beta-strand D. In conclusion, the biochemical and structural properties of G6PD(p.Gly163Ser) and G6PD(WT) enzymes are significantly different, which may be responsible for clinical diversity of G6PD deficiencies. (Lu et al, 2011; PMID: 22165289) (PS3_moderate). This variant is located in the conserved binding domain of the G6PD protein (PM1). This variant is a missense change at an amino acid residue where the different missense change p.Gly163Asphas been seen before (PMID:8364584) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs137852314) and in the HGMD database: CM890050. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 10367).
Baylor Genetics	RCV003466846	SCV004195393	pathogenic	Malaria, susceptibility to	2023-09-27	criteria provided, single submitter	clinical testing
OMIM	RCV000011085	SCV000031312	other	G6PD MAHIDOL	2017-05-24	no assertion criteria provided	literature only