ClinVar Miner

Submissions for variant NM_000402.4(G6PD):c.221C>G (p.Ala74Gly) (rs78478128)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699943 SCV000828676 pathogenic Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 44 of the G6PD protein (p.Ala44Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. 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 (PMID: 8533762, 15315792, 20621077, 22906047, 26829728, 27880809). ClinVar contains an entry for this variant (Variation ID: 10406). Experimental studies have shown that this missense change reduces G6PD enzymatic activity in vitro (PMID: 8533762). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000699943 SCV001142116 uncertain significance Anemia, nonspherocytic hemolytic, due to G6PD deficiency 2019-05-28 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 2019-11-08 criteria provided, single submitter clinical testing Also known as G6PD Orissa (Kaeda et al., 1995; Sarker et al., 2016); Functional analysis of recombinant enzyme showed significantly increased Km-NADP and increased thermostability (Kaeda et al., 1995); This variant is associated with the following publications: (PMID: 8533762, 27880809, 21446359, 12497642, 26021654, 26139767, 26829728, 2255919, 15315792, 20621077, 30097005, 21931771, 21507207)
OMIM RCV000011149 SCV000031376 other G6PD ORISSA 2013-04-18 no assertion criteria provided literature only

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