ClinVar

Description

Variant summary: HBB c.283G>A (p.Asp95Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251420 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.283G>A (aka Hb Bunbury), is a known high oxygen affinity hemoglobin variant, and is reported in several asymptomatic heterozygotes, with or without compensatory erythrocytosis (Como_1983, Li_1990, Ballas_1992, Walker_2007, Oliveira_2018). To our knowledge, no homozygous occurrences or compound heterozygosity with pathogenic HBB variants were reported, therefore no clear conclusions about association of the variant with Hemoglobinopathy can be made. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant doesn't affect stability, however results in an increase in oxygen affinity, a moderate decrease in cooperativity and a reduced Bohr effect (Como_1983, Ballas_1992, Walker_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.