ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508438 SCV000601297 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000999918 SCV000603929 pathogenic not specified 2018-08-30 criteria provided, single submitter clinical testing The Hb O-Arab variant (HBB: c.364G>A; p.Glu122Lys, also known as Glu121Lys when numbered from the mature protein, rs33946267) is not associated with clinical manifestations in heterozygous carriers but can cause sickling disease when found in trans to Hb S or Hb C (Milner 1970, Ramot 1960, Rossi 2011, Zimmerman 1999, HbVar database and references therein). This variant has also been reported in cis to Hb S in a doubly substituted variant known as Hb S-Oman (Langdown 1989, HbVar database and references therein) which causes red cell sickling and has been reported in heterozygous individuals either with sickle cell disease or that were asymptomatic, though individuals with less severe clinical symptoms often had alpha thalassemia trait (Al Balushi 2017, Nagel 1998). Functional characterization of the Hb O-Arab variant globin in the presence of Hb S indicates that the Hb S/Hb O-Arab hemoglobin precipitates at a lower concentration that Hb S/Hb S or HbS/Hb A, suggestive of a strong sickling effect (Milner 1970). Hb O-Arab is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 15292), and it is found in the general population with an overall allele frequency of 0.001% (4/282706 alleles) in the Genome Aggregation Database. Based on available information, the variant is considered to be 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 Link to HbVar database for Hb S-Oman: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=687 Al Balushi HWM et al. The super sickling haemoglobin HbS-Oman: a study of red cell sickling, K+ permeability and associations with disease severity in patients heterozygous for HbA and HbS-Oman (HbA/S-Oman genotype). Br J Haematol. 2017 Oct;179(2):256-265. Langdown JV et al. A new doubly substituted sickling haemoglobin: HbS-Oman. Br J Haematol. 1989 Mar;71(3):443-4. 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. Nagel RL et al. HbS-oman heterozygote: a new dominant sickle syndrome. Blood. 1998 Dec 1;92(11):4375-82. 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.
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.
Baylor Genetics RCV000202511 SCV001163644 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000029993 SCV001194054 pathogenic beta Thalassemia 2019-12-17 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.364G>A(E122K, aka Hb O-Arab) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with hemoglobin O-Arab. Sources cited for classification include the following: PMID 1112610, 893136 and 5481775. Classification of NM_000518.4(HBB):c.364G>A(E122K, aka Hb O-Arab) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000508438 SCV001228754 pathogenic not provided 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 122 of the HBB protein (p.Glu122Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs33946267, ExAC no frequency). This variant has been observed in individual(s) with sickle cell anemia (PMID: 5481775, 3859465). It has also been observed to segregate with disease in related individuals. This variant is also known as HbO-Arab or p.Glu121Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 15292, 446736, 446746). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Glu122 amino acid residue in HBB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25666204, 24616059, 24245819). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000202511 SCV001423601 likely pathogenic Hb SS disease 2018-05-09 criteria provided, single submitter clinical testing [ACMG/AMP: PS4, PM2, PM3, PP5] This alteration has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
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
Integrated Genetics/Laboratory Corporation of America RCV000029993 SCV000052648 pathogenic beta Thalassemia 2015-04-03 no assertion criteria provided clinical testing
GeneReviews RCV000202511 SCV000190692 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only

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