ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.266T>C (p.Leu89Pro) (rs33940204)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757364 SCV000885557 pathogenic not provided 2017-10-01 criteria provided, single submitter clinical testing The Hb Santa Ana variant (HBB: c.266T>C; Leu88Pro) (rs33940204) has been reported in a heterozygous state in multiple individuals with hemolytic anemia, jaundice and splenomegaly (Fairbanks 1969, Opfell 1968, HbVar database and references therein). It has also been reported as a de-novo alteration in an affected individual, which co-segregated with clinical symptoms in the subsequent generation (Opfell 1968). Functional characterization of the variant hemoglobin indicates reduced stability and increased formation of inclusion bodies, while tetramers containing the variant hemoglobin are bound to two heme groups instead of four (Opfell 1968). Another missense variant at this position, Leu88Arg, has also been implicated as an unstable hemoglobin resulting in similar clinical symptoms when found in a heterozygous state (Hollender 1969). The Leu88Pro variant is listed in ClinVar (Variation ID: 15343), but is not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The leucine at position 88 is highly conserved (Alamut v2.10), and is located in the heme-binding pocket of the protein (Hollender 1969, Opfell 1968). Computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the Leu88Pro variant has an impact on HBB protein structure or function. Based on the above information, the Hb Santa Ana variant is classified as pathogenic. References: Link to HbVar database for Hb Santa Ana: Fairbanks V et al. Three families with unstable hemoglobinopathies (Köln, Olmsted and Santa Ana) causing hemolytic anemia with inclusion bodies and pigmenturia. Am J Med. 1969; 46(3):344-59. Hollender A et al. New unstable haemoglobin borås: beta 88 (F4) leucine-arginine. Nature. 1969; 222(5197):953-5. Opfell R et al. Hereditary non-spherocytic haemolytic anaemia with post-splenectomy inclusion bodies and pigmenturia caused by an unstable haemoglobin Santa Ana-beta-88 (F4) leucine--proline. J Med Genet. 1968; 5(4):292-7.
OMIM RCV000016586 SCV000036855 other HEMOGLOBIN SANTA ANA 2017-12-12 no assertion criteria provided literature only

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