IthaID: 1076
Names and Sequences
| Functionality: | Globin gene causative mutation | Pathogenicity: | Variant of Uncertain Significance |
|---|---|---|---|
| Common Name: | CD 82 AAG>AAC | HGVS Name: | HBB:c.249G>C |
| Hb Name: | Hb Providence | Protein Info: | β 82(EF6) Lys>Asn |
Context nucleotide sequence:
GCCTGGCTCACCTGGACAACCTCAA [G>C] GGCACCTTTGCCACACTGAGTGAGC (Strand: -)
Protein sequence:
MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLNGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
Also known as:
Comments: Hb Providence occurs in the red cells in two forms; Hb Providence Asn (asparagine) and Hb Providence Asp (aspartic acid), the latter resulting from the post-translational deamidation of the substituted asparagine residue. The amino acid change occurs at the EF6 position of the β chains that is normally occupied by an invariant lysyl residue (β82 (EF6) Lys). This position normally serves as a binding site for 2,3-diphosphoglycerate (2,3-DPG) and chloride. The replacement of Lys by Asn or Asp reduces the net positive charge of this site, which causes a weakening in the interaction with 2,3-DPG and, in turn, stabilizes the T-state conformation and decreases hemoglobin affinity for oxygen. This occurs without a concomitant change in the degree of cooperativity. Hb Providence Asp is the faster abnormal Hb component as seen by electrophretic methods and column chromatography. The parial binding of 2,3-DPG to Hb Providence Asn limits the deamidation process, which results in the Asp form making about two thirds of the Hb Providence in the red cells of carriers. Reported as a β82 AAG>AAC change by bidirectional sequence analysis.
We follow the HGVS sequence variant nomenclature and IUPAC standards.
Phenotype
| Hemoglobinopathy Group: | Structural Haemoglobinopathy |
|---|---|
| Hemoglobinopathy Subgroup: | β-chain variant |
| Allele Phenotype: | N/A |
| Stability: | N/A |
| Oxygen Affinity: | Decreased Oxygen Affinity |
| Associated Phenotypes: | N/A |
Location
| Chromosome: | 11 |
|---|---|
| Locus: | NG_000007.3 |
| Locus Location: | 70973 |
| Size: | 1 bp |
| Located at: | β |
| Specific Location: | Exon 2 |
Other details
| Type of Mutation: | Point-Mutation(Substitution) |
|---|---|
| Effect on Gene/Protein Function: | N/A |
| Ethnic Origin: | Japanese | African |
| Molecular mechanism: | Altered 2,3-DPG binding site |
| Inheritance: | Dominant |
| DNA Sequence Determined: | Yes |
HPLC
| ID | Hb Variant | Gene | Instrument | Method | Area (%) | Ret Time (min) | Comments | ||
|---|---|---|---|---|---|---|---|---|---|
| 101 | Hb Providence | β | D-10 | Dual Kit Program | 16.4 | 0.97 | This variant is spontaneously deaminated X-Asn 13-19%; X-Asp 32-33% leading to several fast eluting peaks. | [PDF] | |
| 606 | Hb Providence | β | D-10 | Dual Kit Program | 31.3 | 0.3 | This variant is spontaneously deaminated X-Asn 13-19%; X-Asp 32-33% leading to several fast eluting peaks. | [PDF] | |
| 607 | Hb Providence | β | D-10 | Dual Kit Program | 16.4 | 0.97 | This variant is spontaneously deaminated X-Asn 13-19%; X-Asp 32-33% leading to several fast eluting peaks. | [PDF] |
In silico pathogenicity prediction
Publications / Origin
- Moo-Penn WF, Jue DL, Bechtel KC, Johnson MH, Schmidt RM, Hemoglobin Providence. A human hemoglobin variant occurring in two forms in vivo., The Journal of biological chemistry, 251(23), 7557-62, 1976
- Bonaventura J, Bonaventura C, Sullivan B, Ferruzzi G, McCurdy PR, Fox J, Moo-Penn WF, Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82., J Biol Chem, 251(23), 7563-71, 1976
- Charache S, Fox J, McCurdy P, Kazazian H, Winslow R, Hathaway P, van Beneden R, Jessop M, Postsynthetic deamidation of hemoglobin Providence (beta 82 Lys replaced by Asn, Asp) and its effect on oxygen transport., J Clin Invest, 59(4), 652-8, 1977
- Bardakjian J, Leclerc L, Blouquit Y, Oules O, Rafaillat D, Arous N, Bohn B, Poyart C, Rosa J, Galacteros F, A new case of hemoglobin Providence (alpha 2 beta 2 82 (EF6) Lys----Asn or Asp) discovered in a French Caucasian family. Structural and functional studies., Hemoglobin, 9(4), 333-48, 1985
- Newman CN, Litwin CM, Bowlby DA, Lewis KA, Paulo RC, Hemoglobin Providence (β82 Lys > Asn, Asp) and lower-than-expected HbA1c in a nonadherent teenager with type 1 diabetes: a case report and literature review., Clin Case Rep, 5(12), 2000-2002, 2017