ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.364G>A (p.Glu122Lys) (rs33946267)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508438 SCV000603929 pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing The Hb O-Arab variant (HBB: c.364G>A, Glu121Lys) (rs33946267) is not associated with clinical manifestations in heterozygous carriers, but can cause sickling disease when found in-trans with Hb S or Hb C (Milner 1970, Ramot 1960, Rossi 2010, Zimmerman 1999, HbVar database and references therein). Functional characterization of the variant globin in the presence of Hb S indicates that the Hb S/Hb O-Arab hemoglobin precipitates at a lower concentration than Hb S/Hb S or HbS/Hb A, suggestive of a strong sickling effect (Milner 1970). The variant is listed in ClinVar (Variation ID: 15292), and observed in the general population at a frequency of 0.001% in the Genome Aggregation Database (3/246068 alleles). Based on available information, this variant is considered pathogenic. REFERENCES Link to HbVar database for Hb O-Arab: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=510 Milner P et al. Hemoglobin O arab in four negro families and its interaction with hemoglobin S and hemoglobin C. N Engl J Med. 1970; 283(26):1417-25. Ramot B et al. Haemoglobin O in An Arab Family. Br Med J. 1960; 2(5208):1262-4. Rossi P et al. Bone marrow necrosis and sickle cell crisis associated with double heterozygosity for HbS and HbOARAB. Am J Hematol. 2011; 86(3):309-10. Zimmerman S et al. Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol. 1999; 60(4):279-84.
GeneReviews RCV000202511 SCV000190692 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000029993 SCV000052648 pathogenic beta Thalassemia 2015-04-03 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587075 SCV000697126 pathogenic Sickle cell-Hemoglobin O Arab disease 2016-08-22 criteria provided, single submitter clinical testing Variant summary: The HBB c.364G>A (p.Glu122Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). this missense variant, also called Hb O-Thrace or Egypt, is a well-known variant that associates with Hb O disease (sickle cell disease and beta-thalassemia). When variant is seen in homozygous state, it does not cause BTHAL, but instead a mild anemia. When seen in trans with Hb S, it causes severe SICKLE disease similar to Hb S homozyotes. When seen in trans with BTHAL DV, it causes a mild to moderately severe anemia (which can have similarities to BTHAL-intermedia) which is worse than the anemia seen in Hb O homozygotes. Studies (Milner_NEJM_1970 and Rachmilewitz_HumGenet_1985) have shown hemoglobin function was impaired in patients with compound het for Hb O-Arab and Hb S. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000016524 SCV000036792 other HEMOGLOBIN O (ARAB) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016525 SCV000036793 other HEMOGLOBIN EGYPT 2017-12-12 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508438 SCV000601297 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing

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