ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.431A>C (p.His144Pro) (rs33918338)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001407 SCV001158641 pathogenic not specified 2019-06-20 criteria provided, single submitter clinical testing The Hb Syracuse variant (HBB: c.431A>C; p.His144Pro, also known as His143Pro when numbered from the mature protein; rs33918338) is reported in the literature in the heterozygous state in several individuals affected with erythrocytosis (Gonzalez Fernandez 2009, Jensen 1975, HbVar database). At least one individual with this variant had multiple family members with erythrocytosis (Jensen 1975), and its occurrence in heterozygous affected individuals suggests it acts in a dominant manner (Gonzalez Fernandez 2009, Jensen 1975, HbVar database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at codon 144 is highly conserved, occurs in the functionally important 2,3-diphosphoglycerate binding site (Wajcman 2005), and functional studies indicate this variant exhibits increased oxygen affinity (Jensen 1975). Additionally, other amino acid substitutions at this codon (p.His144Gln, p.His144Arg) exhibit increased oxygen affinity and are associated with erythrocytosis (Camps 2016, Venkateswaran 2005, Wajcman 2005). Based on available information, the Hb Syracuse variant is considered to be pathogenic. References: HbVar link for Hb Syracuse: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=564 Camps C et al. Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica. 2016 Nov;101(11):1306-1318. Gonzalez Fernandez FA et al. Haemoglobinopathies with high oxygen affinity. Experience of Erythropathology Cooperative Spanish Group. Ann Hematol. 2009 Mar;88(3):235-8. Jensen M et al. Hemoglobin Syracuse (alpha2beta2-143(H21)His leads to Pro), a new high-affinity variant detected by special electrophoretic methods. Observations on the auto-oxidation of normal and variant hemoglobins. J Clin Invest. 1975 Mar;55(3):469-77. Venkateswaran L et al. Homozygous hemoglobin Abruzzo in a North American child. J Pediatr Hematol Oncol. 2005 Nov;27(11):618-20. 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 RCV000016616 SCV000036885 other HEMOGLOBIN SYRACUSE 2017-12-12 no assertion criteria provided literature only
OMIM RCV000641613 SCV000763255 pathogenic Erythrocytosis 6, familial 1975-03-01 no assertion criteria provided literature only

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