ClinVar Genomic variation as it relates to human health

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.

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.

[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].

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 122 of the HBB protein (p.Glu122Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sickle cell anemia (PMID: 3859465, 5481775). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as HbO-Arab or p.Glu121Lys. ClinVar contains an entry for this variant (Variation ID: 15292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. 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: 24245819, 24616059, 25666204). 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.

The Hb O-Arab variant (HBB: c.364G>A; p.Glu122Lys, also known as Glu121Lys when numbered from the mature protein, rs33946267, HbVar ID: 510) 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 (HbVar ID: 687, 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: https://globin.bx.psu.edu/hbvar/menu.html 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. PMID: 28699687. Langdown JV et al. A new doubly substituted sickling haemoglobin: HbS-Oman. Br J Haematol. 1989 Mar;71(3):443-4. PMID: 2930724. 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. PMID: 5481775 Nagel RL et al. HbS-oman heterozygote: a new dominant sickle syndrome. Blood. 1998 Dec 1;92(11):4375-82. PMID: 9834244. Ramot B et al. Haemoglobin O in An Arab Family. Br Med J. 1960; 2(5208):1262-4. PMID: 20788973. 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. PMID: 20954261. Zimmerman S et al. Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol. 1999; 60(4):279-84. PMID: 10203101.