ClinVar

Description

Variant summary: HBB c.389C>T (p.Ala130Val), also referred to in the literature as Hb La Desirade, results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes. c.389C>T has been observed in asymptomatic carriers (Alkindi_2021) and in compound heterozygosity with HbS (c.20A>T (p.Glu7Val)) in multiple individuals who were affected with mild sickle cell anemia (Merault_1986, Alkindi_2021). However, the variant has also been reported in compound heterozygosity with HbC (c.19G>A (p.Glu7Lys)), and HbE (c.79G>A (p.Glu27Lys)), in clinically asymptomatic individuals (Merault_1986, Kamseng_2017). To our knowledge, no homozygous occurrence has been reported, however, the variant was found together with a beta-0-thal variant in a clinically asymptomatic individual, who had elevated reticulocyte count (Merault_1986). These data indicate that the variant may be associated with a milder disease phenotype, which is dependent on the variant in trans. At least one publication reported experimental evidence indicating that the variant results in a mild decrease in oxygen affinity and precipitation during the isopropanol test, suggestive of an unstable hemoglobin (Merault 1986). The following publications have been ascertained in the context of this evaluation (PMID: 20437613, 33489049, 32411010, 25677748, 26635043, 27670359, 15727901, 17932132, 3557994, 22995479, 26594346, 37845805, 31553106, 35143361). ClinVar contains an entry for this variant (Variation ID: 15245). Based on the evidence outlined above, the variant was classified as likely pathogenic.