Submissions for variant NM_000402.4(G6PD):c.221C>G (p.Ala74Gly)

dbSNP: rs78478128

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000699943	SCV000828676	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 44 of the G6PD protein (p.Ala44Gly). This variant is present in population databases (rs78478128, 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 glucose-6-phosphate dehydrogenase deficiency (PMID: 10192449, 17524386). It is commonly reported in individuals of South Asian ancestry (PMID: 8533762, 15315792, 20621077, 22906047, 26829728, 27880809). ClinVar contains an entry for this variant (Variation ID: 10406). 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: 8533762). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000699943	SCV001142116	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-05-27	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000699943	SCV001443094	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	This variant in exon 3 of the G6PD gene results in the amino acid substitution from Alanine to Glycine at codon 74 (p.Ala74Gly) with the sequence change of c.221C>G (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 reference base is conserved across the species and in-silico predictions by SIFT and MutationTaster are damaging. The Missense Variants Z-Score for this variant is 2.60. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. The G6PD c.221C>G; p.Ala74Gly variant, also referred to as c.131C>G; p.Ala44Gly, commonly known as G6PD Orissa, has been described in literatures as a Class III variant, associated with moderate enzyme deficiency (Arunachalam et al., 2020; PMID: 32425388, Minucci et al., 2010; PMID: 20621077). This variant has previously been reported for glucose-6-phosphate dehydrogenase deficiency and is most frequent in Indian tribal population (Kaeda et al., 1995; PMID:8533762, Sukumar et al., 2004; PMID:15315792, Lin et al., 2016; PMID:26829728, Sarker et al., 2016; PMID:27880809). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995; PMID:8533762).
GeneDx	RCV001538639	SCV001756317	pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Functional analysis of recombinant enzyme showed significantly increased Km-NADP and increased thermostability (Kaeda et al., 1995); Also known as G6PD Orissa (Kaeda et al., 1995; Sarker et al., 2016); This variant is associated with the following publications: (PMID: 21507207, 27880809, 21931771, 8533762, 30097005, 20621077, 15315792, 2255919, 26829728, 26139767, 26021654, 12497642, 21446359, 33069889, 12215013)
Revvity Omics, Revvity	RCV000699943	SCV002025187	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2022-12-27	criteria provided, single submitter	clinical testing
Dunham Lab, University of Washington	RCV000699943	SCV002599317	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 and jaundice (PP4, PS4_M). In one family, hemiygote and heterozygous mother both have decreased G6PD activity (PP1). Decreased activity in red blood cells (5-33%) (PS3). In GxxGDLA NADP binding site (PM1). Predicted to be damaging by SIFT and MutationTaster, and probably damaging by PolyPhen (PP3). Below expected carrier frequency in gnomAD (PM2). Post_P 0.999 (odds of pathogenicity 13661, Prior_P 0.1).
CeGaT Center for Human Genetics Tuebingen	RCV001538639	SCV004011707	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	G6PD: PM1:Strong, PM5, PS3:Moderate, PS4:Moderate
Illumina Laboratory Services, Illumina	RCV003314551	SCV004014691	pathogenic	G6PD deficiency	2023-05-03	criteria provided, single submitter	clinical testing	The G6PD c.221C>G (p.Ala74Gly) missense variant, also known as c.131C>G (p.Ala44Gly) or the G6PD Orissa allele, has been commonly reported in individuals with glucose-6-phosphate dehydrogenase deficiency with South Asian ancestry, including in a hemizygous and homozygous state (PMID: 27880809; 8533762; 32425388). Enzyme activity in individuals with this variant is typically 5%-20% of normal. The highest frequency of this allele in the Genome Aggregation Database is 0.004917 in the South Asian population, which includes eight hemizygotes (version 3.1.2). This frequency is consistent with disease prevalence estimates. Functional studies of purified enzyme have demonstrated that this variant causes an increase in Km for NADP+, which results in a reduced G6PD enzyme activity level (PMID: 8533762). This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.221C>G (p.Ala74Gly) variant is classified as pathogenic for glucose-6-phosphate dehydrogenase deficiency.
Neuberg Centre For Genomic Medicine, NCGM	RCV000699943	SCV004046941	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency		criteria provided, single submitter	clinical testing	The missense c.221C>G (p.Ala74Gly) variant in G6PD gene has been reported in heterozygous state in individuals affected with hemolytic anemia. This variant has been reported to be a common cause of the glucose-6-phosphate dehydrogenase in South Asia, although it has also been reported in other populations (Sukumar et al., 2004). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (Kaeda et al., 1995). This variant is reported with the allele frequency 0.01% in the gnomAD and 0.02% in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic / Uncertain Significance. The amino acid Ala at position 74 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala74Gly in G6PD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003466851	SCV004195404	pathogenic	Malaria, susceptibility to	2024-03-23	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000699943	SCV005068209	pathogenic	Anemia, nonspherocytic hemolytic, due to G6PD deficiency	2024-06-22	criteria provided, single submitter	clinical testing	A heterozygous missense variation in exon 3 of the G6PD gene that results in the amino acid substitution of Glycine for Alanine at codon 44 was detected. The observed variant c.131C>G (p.Ala44Gly) has a minor allele frequency of 0.03%, 0.01%, 0.02% and 0.003% in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and topmed databases, respectively. The insilico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of pathogenic.
OMIM	RCV000011149	SCV000031376	other	G6PD ORISSA	2013-04-18	no assertion criteria provided	literature only
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV001538639	SCV004174971	likely pathogenic	not provided	2021-06-24	no assertion criteria provided	clinical testing