ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.79G>A (p.Glu27Lys) (rs33950507)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000496072 SCV000584092 pathogenic beta Thalassemia 2015-02-10 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000521111 SCV000603907 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The Hb E variant (HBB: c.79G>A, Glu26Lys) is a common pathogenic beta globin (HBB) variant. Functional characterization of the variant indicates aberrant splicing of the beta globin mRNA, leading to reduced mature protein (Orkin 1982). Heterozygous Hb E is a clinically benign condition associated with mild microcytosis and target cells without anemia. Homozygous Hb E is usually a clinically benign condition but can be associated with mild anemia and microcytosis. Hb E in combination with a different pathogenic HBB variant on the opposite chromosome can produce a range of clinical phenotypes (Vichinsky 2007, HbVar database and references therein). REFERENCES Link to HbVar database for Hb E: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=277 Orkin S et al. Abnormal RNA processing due to the exon mutation of beta E-globin gene. Nature. 1982; 300(5894):768-9. Vichinsky E Hemoglobin e syndromes. Hematology Am Soc Hematol Educ Program. 2007:79-83.
GeneDx RCV000521111 SCV000617120 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing The c.79 G>A variant in the HBB gene results in the production of hemoglobin E and can be associated with mild anemia when found in the homozygous state (Masiello et al., 2007; Origa, 2015). In the compound heterozygous state with another HBB variant, c.79 G>A can be associated with either hemoglobin E-beta-thalassemia, which is a clinically variable form of thalassemia, or hemoglobin SE disease (Masiello et al., 2007; Vichinsky et al., 2007; Tubsuwan et al., 2011; Origa, 2015). The c.79 G>A variant is observed in 24/16,512 (0.15%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). Some in-silico splice prediction models predict that c.79 G>A may enhance a cryptic splice donor site upstream of the natural splice donor site in intron 1, which may supplant the natural donor site. RNA studies demonstrate that this variant is associated with slow excision of intron 1 and alternative splicing into exon 1 (Orkin et al., 1982). If c.79 G>A does not alter splicing, it will result in the E27K missense change, also commonly referred to as E26K due to the use of alternative nomenclature. The E27K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.79 G>A as a pathogenic variant.
Counsyl RCV000496072 SCV000678060 pathogenic beta Thalassemia 2015-10-29 criteria provided, single submitter clinical testing The Hb E mutation is associated with hemoglobin E.
Integrated Genetics/Laboratory Corporation of America RCV000506024 SCV000697150 pathogenic not specified 2016-04-22 criteria provided, single submitter clinical testing Variant Summary: HBB c.79G>A occurs at a non-conserved position and results in an amino acid change from Glu to Lys. in silico tools predict a damaging outcome, and functional studies show that while HbE has normal oxygen affinity, HbE is correlated with elevated reactive oxygen species and mild oxidative stress. Additionally, splicing studies show that only 5-8% of the mRNA is correctly spliced because this base substitution creates a splice donor site within the exon, leading to loss of the last 16 bases of the exon. The observed allele frequency in controls is 35/121356 (1/3467), but c.79G>A is a known common disease variant. This variant has been reported in homozygous state in hundreds of patients in the literature. Hb E homozygosity results in a mild beta-globin chain deficit which is comparable to that seen in a beta0-thal heterozygote, and typically have a mild hemolytic anemia and mild enlargement of the spleen. However, compound heterozygotes for hemoglobin E/-thalassemia are often severely affected. Conditions in which there is a considerable production of Hb A are milder than those without Hb A. Taken together, this variant is classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778330 SCV000914519 pathogenic Hemoglobin E disease 2018-08-14 criteria provided, single submitter clinical testing The HBB c.79G>A (p.Glu27Lys) variant, also referred to as p.Glu26Lys, is well-described and the singular cause of hemoglobin E disorder (HbE). Though common throughout the world, the p.Glu27Lys variant is found at the greatest frequency in Southeast Asia (Chen et al. 2012). Individuals who are heterozygous for the p.Glu27Lys variant are asymptomatic, while the clinical phenotypes of at least 85 individuals who are homozygous for the variant ranged from asymptomatic to mild to moderate hemolytic microcytic anemia with or without hepatosplenomegaly and jaundice (Prajantasen et al. 2014; Jayasree et al. 2016). Individuals compound heterozygous for p.Glu27Lys and a pathogenic variant for beta-thalassemia can have disease phenotypes ranging from beta-thalassemia intermedia to beta-thalassemia major (Origa et al. 2015). The p.Glu27Lys variant was identified in a compound heterozygous state with a pathogenic beta thalassmia variant in at least 38 individuals who were reported to have mild to moderate thalassemia, 29 of whom required treatment with blood transfusions (Tubsuwan et al. 2011). The variant is reported at a frequency of 0.015152 in the Kinh in Ho Chi Minh City, Vietnam, population of the 1000 Genomes Project. Functionally, the p.Glu27Lys variant is known to produce both a structurally abnormal Hb and a cryptic 5' splice site that causes abnormal mRNA splicing, and transgenic mice exclusively expressing human p.Glu27Lys had red blood cell mild oxidative stress arising in part from the molecular consequences of the p.Glu27Lys variant (Chen et al. 2012). Based on the collective evidence, the p.Glu27Lys variant is classified as pathogenic for hemoglobin E. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000521111 SCV000944706 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 27 of the HBB protein (p.Glu27Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs33950507, ExAC 0.1%). This is the most common variant associated with beta-thalassemia worldwide, and is particularly enriched in Southeast Asian populations (PMID: 21732929, 26554862). It is also known as Hb E or Glu26Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 15161). Experimental studies have shown that this missense change disrupts the structure of the hemoglobin chain, and also creates a cryptic splice site which can lead to a premature termination codon (PMID: 21732929, 22260787). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853358 SCV000996225 pathogenic Anemia 2018-12-10 criteria provided, single submitter clinical testing The c.79G>A variant is observed in 35/30782 (0.11%) alleles from individuals of South Asian background in the gnomAD population database. In silico splice prediction models predict that c.79G>A may enhance a cryptic splice donor site upstream of the natural splice donor site in intron 1, which may supplant the natural donor site. RNA studies demonstrate that this variant is associated with slow excision of intron 1 and alternative splicing into exon 1 (PMID 7177196). If c.79G>A does not alter splicing, it will result in the E27K missense change, also commonly referred to as E26K due to the use of alternative nomenclature. The E27K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Based on the available evidence, the c.79G>A, p.Glu27Lys is classified as Pathogenic.
OMIM RCV000016329 SCV000036597 other Hemoglobin E 2019-07-16 no assertion criteria provided literature only
OMIM RCV000016330 SCV000036598 pathogenic Beta-plus-thalassemia 2009-11-03 no assertion criteria provided literature only
OMIM RCV000016331 SCV000036599 pathogenic Hemoglobin E/beta thalassemia disease 2009-11-03 no assertion criteria provided literature only
OMIM RCV000016332 SCV000036600 protective Malaria, resistance to 2009-11-03 no assertion criteria provided literature only
GeneReviews RCV000202534 SCV000190690 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only

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