|(A;T)||4||carrier of, but unaffected by, sickle cell anemia; greater malaria resistance|
|(AG;AG)||0||common in clinvar|
|(T;T)||5||sickle cell anemia|
This position causes sickle cell anemia
It is an ambiguous flip and is very prone to confusion
dbSNP uses the minus orientation
- rs334(A) encodes the normal Hb A form of (adult) hemoglobin.
- rs334(T) encodes the sickling form of hemoglobin, Hb S.
23andMe tests this snp under the name i3003137 on the plus orientation
- i3003137(T) encodes the normal Hb A form of (adult) hemoglobin.
- i3003137(A) encodes the sickling form of hemoglobin, Hb S.
Only individuals homozygous for this allele, in other words having the rs334(T;T) genotype, will have sickle cell anemia. The (T) allele appears to have maintained through evolution due to the ~10 fold higher resistance to life-threatening forms of malaria that heterozygotes (rs334(A;T) genotypes) exhibit.
See the SNPedia sickle cell anemia entry for more information.
[PMID 20128890] Loss of balancing selection in the betaS globin locus
[PMID 20552021] Haptoglobin and sickle cell polymorphisms and risk of active trachoma in gambian children[PMID 16637741] Seasonal Childhood Anaemia in West Africa Is Associated with the Haptoglobin 2-2 Genotype
[PMID 22506028] Haplotype Analyses of Haemoglobin C and Haemoglobin S and the Dynamics of the Evolutionary Response to Malaria in Kassena-Nankana District of Ghana
[PMID 22574149] Underlying Factors Associated with Anemia in Amazonian Children: A Population-Based, Cross-Sectional Study
[PMID 17668374] Combining evidence of natural selection with association analysis increases power to detect malaria-resistance variants.
[PMID 17688704] Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations.
[PMID 19145247] Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations.
[PMID 19281305] Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.
[PMID 20226094] Myosin individualized: single nucleotide polymorphisms in energy transduction.
[PMID 20585394] Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children.
|qualified_impact||High clinical importance, pathogenic|
|summary||HB-S variant responsible for causing Sickle Cell Disease when homozygous (residue count follows p.HBB). This is often also referred to as E6V, referring to the position of the amino acid in the final protein product (the first amino acid is removed after translation). Heterozygotes have Sickle Cell Trait.|
[PMID 5509617] Hemoglobin G Makassar: beta-6 Glu leads to Ala.
[PMID 12403489] Hb G-Makassar [beta6(A3)Glu-->Ala; codon 6 (GAG-->GCG)]: molecular characterization, clinical, and hematological effects.