ClinVar Genomic variation as it relates to human health

Variant summary: G6PD c.[292G>A;466A>G], p.[Val98Met;Asn156Asp] is a complex allele variant located in the glucose-6-phosphate dehydrogenase, NAD-binding domain of the encoded protein sequence. In the literature, it is known as G6PD A- haplotype and can also be found under the nomenclature c.[202G>A;376A>G], p.[Val68Met;Asn126Asp]. G6PD A- haplotype is reported to be most prevalent in the African population (examples: Town_1992, Enevold_2005, Gomez-Gallego_2000, Shah_2014) and it is stated to cause susceptibility to the hemolytic effect of drugs and appears to confer resistance to falciparum malaria in female heterozygotes (Beutler_1989). The allele frequency of this variant could not be determined from population databases such as gnomAD as it is a multinucleotide variant consisting of X-153764217-C-T (c.292G>A; p.Val98Met) and X-153763492-T-C (c.466A>G; p.Asn156Asp). The individual variants have variable frequencies and the exact number of alleles representing a combination of the two in cis is unknown. However, based on the frequency of the least prevalent allele, namely (c.292G>A; p.Val98Met), it can be estimated that the multinucleotide variant will be found at a frequency of 0.0091 in 183313 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database (v2.1.1) including 351 hemizygotes. The variant has been reported in multiple individuals (both African and from other ethnic backgrounds) affected with Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency (examples: Beutler_1989, Dallol_2012). In functional studies, this complex allele was determined to lead to a protein with decreased stability and to cause reduced enzymatic activity compared to controls (examples: Vulliamy_1988, Beutler_1989, Gomez-Gallego_2000). Town et al (1992) report that the two variants in this complex allele act synergistically to cause instability of the protein molecule leading to loss in enzyme activity. The following publications have been ascertained in the context of this evaluation (PMID: 2572288, 23006493, 16356170, 10734064, 9858856, 25201310, 1303173, 3393536). ClinVar contains an entry for this variant (Variation ID: 10361). Based on the evidence outlined above, the variant was classified as pathogenic.