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

gnomAD frequency: 0.00006  dbSNP: rs33950507

Total submissions: 27

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	2023-11-27	criteria provided, single submitter	clinical testing	The Hb E variant (HBB: c.79G>A; p.Glu27Lys, also known as Glu26Lys when numbered from the mature protein, rs33950507, HbVar ID: 277) is a common pathogenic beta globin 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: https://globin.bx.psu.edu/hbvar/hbvar.html Orkin S et al. Abnormal RNA processing due to the exon mutation of beta E-globin gene. Nature. 1982; 300(5894):768-9. PMID: 7177196. Vichinsky E Hemoglobin e syndromes. Hematology Am Soc Hematol Educ Program. 2007:79-83. PMID: 18024613.
GeneDx	RCV000521111	SCV000617120	pathogenic	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Published functional RNA studies demonstrate that this variant is associated with slow excision of intron 1 and alternative splicing into exon 1 (Orkin et al., 1982); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25370867, 12144064, 15481886, 22975760, 18024613, 6166632, 24123366, 6198908, 3728469, 29669226, 22028795, 22260787, 7177196, 26554862, 12149194, 24368026, 17278112, 27834070, 9140717, 7583766, 31553106, 1878422, 31980526, 30275481, 31589614, 10870880, 31890591, 8629114, 28674233, 34794358, 33092414, 29251006, 28671035, 35047849, 21732929)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002288495	SCV000697150	pathogenic	Beta-thalassemia HBB/LCRB	2024-01-05	criteria provided, single submitter	clinical testing	Variant summary: HBB c.79G>A (p.Glu27Lys), also known as Hb E, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: three predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that only 5-8% of mRNA is correctly spliced due to the creation of a cryptic splice donor site, leading to the loss of the last 16 bases of the exon (e.g., Chen_2012). The variant allele was found at a frequency of 0.00025 in 251352 control chromosomes in the gnomAD database, including 1 homozygotes, but c.79G>A is a known, common disease variant. This variant has been reported in the homozygous state in numerous patients in the literature (e.g., Pakdee_2014, Sanchaisuriya_2006). Hb E homozygosity results in a mild beta-globin chain deficit which is comparable to that seen in beta0-thal heterozygotes, and homozygotes typically have 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. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in increased reactive oxygen species as well as mild oxidative stress (e.g., Chen_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22260787, 24581976, 16750922). ClinVar contains an entry for this variant (Variation ID: 15161). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, 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	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 27 of the HBB protein (p.Glu27Lys). This variant is present in population databases (rs33950507, gnomAD 0.1%). This missense change has been observed in individual(s) with beta thalassemia (PMID: 21732929, 26554862). It has also been observed to segregate with disease in related individuals. This variant is also known as Hb E and Glu26Lys. ClinVar contains an entry for this variant (Variation ID: 15161). 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. Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (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.
Baylor Genetics	RCV000202534	SCV001163289	pathogenic	Hb SS disease	2022-03-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000496072	SCV001193841	pathogenic	beta Thalassemia	2019-11-18	criteria provided, single submitter	clinical testing	NM_000518.4(HBB):c.79G>A(E27K, aka Hb E) is classified as pathogenic and is associated with hemoglobin E disease. Sources cited for classification include the following: PMID: 17278112, 7177196, 7395858, 22028795, 6166632, and 24368026. Classification of NM_000518.4(HBB):c.79G>A(E27K, aka Hb E) 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000521111	SCV001449845	pathogenic	not provided	2015-12-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000496072	SCV001530442	pathogenic	beta Thalassemia	2018-01-31	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV001536065	SCV001752762	pathogenic	Dominant beta-thalassemia; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6	2021-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000521111	SCV002024962	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000506024	SCV002517170	pathogenic	not specified	2022-08-08	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288495	SCV002579011	pathogenic	Beta-thalassemia HBB/LCRB	2022-03-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415419	SCV002679417	pathogenic	Inborn genetic diseases	2017-08-08	criteria provided, single submitter	clinical testing	The p.E27K pathogenic mutation (also known as c.79G>A, Hb E, and E26K), located in coding exon 1 of the HBB gene, results from a G to A substitution at nucleotide position 79. The glutamic acid at codon 27 is replaced by lysine, an amino acid with similar properties. Hb E is a common hemoglobin variant prevalent among Southeast Asian individuals. The combination of Hb E and beta-thalassemia is frequently associated with a moderately severe phenotype, due to a primary reduction of beta-E-globin synthesis resulting from decreased accumulation of beta-E-globin mRNA (Benz EJ et al. J. Clin. Invest., 1981 Jul;68:118-26). Abnormal RNA processing occurs due to activation of a cryptic splice donor site in exon 1 (Orkin SH et al. Nature, 1982 Dec;300:768-9). Overall, compound heterozygosity for Hb E beta-thalassemia may result in a variable phenotype ranging from asymptomatic to transfusion dependency, though Hb E beta-zero-thalassemia is typically severe and may be similar to thalassemia major or intermedia (Vichinsky E. Hematology Am Soc Hematol Educ Program, 2007;:79-83). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Lifecell International Pvt. Ltd	RCV002288495	SCV003845192	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.79G>A in Exon 1 of the HBB gene that results in the amino acid substitution p.Glu27Lys was identified. The observed variant has a minor allele frequency of 0.00025/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 15161). This variant has been identified in patients affected with beta-thalassemia (Tubsuwan A et al., 2011). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Suma Genomics	RCV002288495	SCV003852613	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002288495	SCV004100544	pathogenic	Beta-thalassemia HBB/LCRB		criteria provided, single submitter	clinical testing	The missense variant p.E27K in HBB (NM_000518.4) causes the same amino acid change as a previously established pathogenic variant. The p.E27K variant is observed in 8/1,008 (0.7937%) alleles from individuals of East Asian background in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415712	SCV004116653	pathogenic	HBB-related condition	2023-05-27	criteria provided, single submitter	clinical testing	The HBB c.79G>A variant is predicted to result in the amino acid substitution p.Glu27Lys. This variant, commonly referred to as Hemoglobin E/HbE, has previously been reported to cause hemoglobinopathy (HbVar; http://globin.bx.psu.edu/hbvar; Vichinsky. 2007. PubMed ID: 18024613). Historically, this variant was reported as p.Glu26Lys (Orkin et al. 1982. PubMed ID: 7177196). In the ClinVar database, this variant has also been interpreted as pathogenic by several different laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/15161/). Homozygous HbE has been reported in many patients and can be associated with mild hemolytic anemia (Masiello et al. 2007. PubMed ID: 17278112; Jayasree et al. 2016. PubMed ID: 26554862; Origa et al. 2018. PubMed ID: 20301599). This variant 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	not provided	Hb SS disease		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000496072	SCV001244657	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000496072	SCV002091596	pathogenic	beta Thalassemia	2018-08-23	no assertion criteria provided	clinical testing