Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001811147 | SCV001472130 | pathogenic | not provided | 2020-01-02 | criteria provided, single submitter | clinical testing | The Hb Bethesda (HBB: c.436T>C; p.Tyr146His, also known as Tyr145His when numbered from the mature protein, rs33949869), is reported in the literature in the heterozygous state in multiple individuals affected with erythrocytosis (see link to HbVar, Franklin 1986, McClure 2006, Tamura 2015, van Zwieten 2014). This variant is reported in ClinVar (Variation ID: 15112), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 146 is highly conserved, and functional analyses of the variant protein show increased oxygen affinity (see link to HbVar, Franklin 1986). Additionally, other amino acid substitutions at this codon (Hb Nancy, Hb Osler, Hb Rainier, Hb McKees Rocks) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar IDs: 571, 572, 573, 574), and several hemoglobin variants with high oxygen affinity leading to erythrocytosis are located at the carboxy-terminal end of the HBB gene (Wajcman 2004). Based on available information, the Hb Bethesda variant is considered to be pathogenic. References: Link to HbVar for Hb Bethesda: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=570 Franklin IM et al. Increasing haemoglobin oxygen affinity to prevent sickling: abnormal haemoglobin variants as models. Br J Haematol. 1986 Oct;64(2):319-29. McClure RF et al. The JAK2 V617F mutation is absent in patients with erythrocytosis due to high oxygen affinity hemoglobin variants. Hemoglobin. 2006;30(4):487-9. Tamura S et al. A Japanese Family with Congenital Erythrocytosis Caused by Haemoglobin Bethesda. Intern Med. 2015;54(18):2389-93. van Zwieten R et al. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. Hemoglobin. 2014;38(1):1-7. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. |
| OMIM | RCV000016267 | SCV000036535 | other | HEMOGLOBIN BETHESDA | 2017-12-12 | no assertion criteria provided | literature only | |
| OMIM | RCV000641411 | SCV000763052 | pathogenic | Erythrocytosis, familial, 6 | 1976-08-01 | no assertion criteria provided | literature only |