ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.79G>A (p.Glu27Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.79G>A (p.Glu27Lys)
Variation ID: 15161 Accession: VCV000015161.133
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226943 (GRCh38) [ NCBI UCSC ] 11: 5248173 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 21, 2015 Aug 11, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.79G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Glu27Lys missense NC_000011.10:g.5226943C>T NC_000011.9:g.5248173C>T NG_000007.3:g.70673G>A NG_042296.1:g.474C>T NG_046672.1:g.4878C>T NG_059281.1:g.5129G>A LRG_1232:g.5129G>A LRG_1232t1:c.79G>A LRG_1232p1:p.Glu27Lys P68871:p.Glu27Lys - Protein change
- E27K
- Other names
- E26K
- CD 26 GAG>AAG [Glu>Lys]
- Canonical SPDI
- NC_000011.10:5226942:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00280 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00025
Exome Aggregation Consortium (ExAC) 0.00029
1000 Genomes Project 0.00280
1000 Genomes Project 30x 0.00281
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HBB | - | - |
GRCh38 GRCh37 |
22 | 1832 | |
LOC106099062 | - | - | - | GRCh38 | - | 860 |
LOC107133510 | - | - | - | GRCh38 | - | 1782 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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other (1) |
no assertion criteria provided
|
Nov 3, 2009 | RCV000016329.16 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 3, 2009 | RCV000016330.40 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 3, 2009 | RCV000016331.37 | |
protective (1) |
no assertion criteria provided
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Nov 3, 2009 | RCV000016332.41 | |
Pathogenic (2) |
criteria provided, single submitter
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Mar 10, 2022 | RCV000202534.13 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2022 | RCV000496072.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 14, 2018 | RCV000778330.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2018 | RCV000853358.9 | |
Pathogenic (1) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2022 | RCV000506024.14 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000521111.34 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 30, 2021 | RCV001536065.11 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 5, 2024 | RCV002288495.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2017 | RCV002415419.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003989105.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2023 | RCV004532365.1 | |
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Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 10, 2015)
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criteria provided, single submitter
Method: research
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584092.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hemoglobin E disease
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914519.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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Anemia
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996225.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 07, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449845.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 8
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Pathogenic
(Jan 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001530442.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Heinz body anemia
Hereditary persistence of fetal hemoglobin Dominant beta-thalassemia Hb SS disease alpha Thalassemia Malaria, susceptibility to Beta-thalassemia HBB/LCRB METHEMOGLOBINEMIA, BETA TYPE Erythrocytosis, familial, 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752762.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021
Comment:
This variant has been detected in individual(s) who were sent for testing of Renasight - kidney gene panel.
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Pathogenic
(Aug 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517170.2
First in ClinVar: May 28, 2022 Last updated: Aug 15, 2022 |
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Pathogenic
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579011.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM3, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 2
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Pathogenic
(Mar 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001163289.2
First in ClinVar: Mar 01, 2020 Last updated: Mar 11, 2023 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003845192.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Comment:
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 … (more)
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. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Suma Genomics
Accession: SCV003852613.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Pathogenic
(Sep 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617120.6
First in ClinVar: Dec 19, 2017 Last updated: Sep 22, 2023 |
Comment:
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., … (more)
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) (less)
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603907.10
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697150.2
First in ClinVar: Sep 30, 2017 Last updated: Mar 30, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847535.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Glu27Lys variant in HBB, also known as p.Glu26Lys and the cause of hemoglobine E disease, has been reported in numerous individuals in the heterozygous … (more)
The p.Glu27Lys variant in HBB, also known as p.Glu26Lys and the cause of hemoglobine E disease, has been reported in numerous individuals in the heterozygous (asymptomatic), homozygous (asymptomatic to mild to moderate hemolytic microcytic anemia with or without hepatosplenomegaly and jaundice) and in the compound heterozygous state with another pathogenic variant for beta-thalassemia (phenotypes ranging from mild to moderate beta-thalassemia (Orkin 1982 PMID: 7177196, Tubsuwan 2011 PMID: 21732929, Prajantasen 2014 PMID: 25370867, Jayasree 2016 PMID: 26554862). It has been reported in ClinVar (Variation ID 15161) and it has been identified in 41/4836 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies showed that this variant produces both a structurally abnormal Hb and creates a cryptic 5' splice site that causes abnormal mRNA splicing; in addition 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 2012 PMID: 22260787). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM3_very Strong, PS3_Strong. (less)
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Pathogenic
(Aug 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002679417.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 18, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193841.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(May 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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HBB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004116653.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024962.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000944706.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
|
|
Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Malaria, susceptibility to
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805856.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100544.2
First in ClinVar: Nov 04, 2023 Last updated: Jul 15, 2024 |
Comment:
The missense c.79G>A(p.Glu27Lys) variant in HBB gene has been reported in both homozygous and heterozygous states in multiple individuals affected with hemoglobin-related disorder (Prajantasen et … (more)
The missense c.79G>A(p.Glu27Lys) variant in HBB gene has been reported in both homozygous and heterozygous states in multiple individuals affected with hemoglobin-related disorder (Prajantasen et al., 2014; Jayasree et al., 2016). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (Chen Q et. al., 2012). This variant is reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Glu27Lys in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a conflicting evidences on protein structure and function for this variant. The amino acid Glu at position 27 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Aug 23, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002091596.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
Pathogenic
(Nov 03, 2009)
|
no assertion criteria provided
Method: literature only
|
BETA-E-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036599.7
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), … (more)
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al. (1984). Orkin et al. (1982) reported the complete nucleotide sequence of a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the only abnormality. Expression of the beta-E gene was tested by introducing it into HeLa cells. Two abnormalities of RNA processing were shown: slow excision of intervening sequence-1 and alternative splicing into exon 1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. Antonarakis et al. (1982) used the Kazazian haplotype approach of analyzing DNA polymorphisms in the beta-globin cluster to present evidence that the beta-E mutation occurred at least twice in Southeast Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could be recognized by the restriction enzyme MnlI which cleaves DNA at the sequence 3-prime-GGAG-5-prime. Rey et al. (1991) described SE disease in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have increased risk of the complications of sickling including pneumococcal sepsis. Rees et al. (1996) reported a girl homozygous for Hb E with severe anemia and anisopoikilocytosis, who was also homozygous for pyrimidine 5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient for P5N, the stability of the Hb E was decreased. Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et al. (2002) examined the possible protective role of Hb E and other prevalent inherited hemoglobin abnormalities against malaria (611162) in Thailand. They assessed the effect of Hb E by means of a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin red blood cells, including those heterozygous and homozygous for Hb E. The heterozygote HbAE cells differed markedly from all the other cells tested, with invasion restricted to approximately 25% of the red blood cells. Despite their microcytosis, AE heterozygous cells were functionally relatively normal in contrast to the red blood cells from the other hemoglobinopathies studied. Chotivanich et al. (2002) interpreted these findings as suggesting that HbAE erythrocytes have an unidentified membrane abnormality that renders most of the red blood cell population relatively resistant to invasion by P. falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and was considered consistent with the 'Haldane hypothesis' of heterozygote protection against severe malaria for Hb E. The Hb E variant is concentrated in parts of Southeast Asia where malaria is endemic, and Hb E carrier status confers some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed biallelic markers surrounding the Hb E variant in a Thai population. Pairwise LD analysis of Hb E and 43 surrounding biallelic markers revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed between non-Hb E variants and the same markers. The inferred haplotype network suggested a single origin of the Hb E variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicated that the Hb E variant arose 1,240 to 4,440 years ago. Thus, the Hb E mutation occurred recently and allele frequency increased rapidly. The study demonstrated that a high resolution LD map across the human genome can detect recent variants that have been subjected to positive selection. The highest frequencies of the Hb E gene in large population samples, approximately 0.3, had been observed in the southern part of northeastern Thailand. Even higher frequencies were observed by Flatz et al. (2004) in Austroasiatic populations in southern Laos. One frequency was as high as 0.433 in a population of Sekong Province. As in other areas of Southeast Asia, hemoglobin E is a very common hemoglobin variant in India, where the highest prevalence of hemoglobin E has been observed in the northeastern regions. In West Bengal, carrier frequency varies from 5 to 35% in different subpopulations, whereas in Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%. Individuals heterozygous for hemoglobin E have normal or near-normal mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in peripheral blood. Homozygosity for hemoglobin E is commonly benign, characterized by mild hypochromic microcytic anemia with the presence of target cells. Edison et al. (2005) observed hyperbilirubinemia among patients with homozygosity for the hemoglobin E gene in the Indian population, with jaundice being the major complaint at presentation. A study of UGT1A1 gene polymorphism showed that the variant TA(7) in the promoter region of the UGT1A1 gene (191740.0011) was associated with hyperbilirubinemia in homozygous HbE patients. The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by P. falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. The estimated number of worldwide annual births of patients with HbE beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall, 2010). (less)
|
|
protective
(Nov 03, 2009)
|
no assertion criteria provided
Method: literature only
|
MALARIA, RESISTANCE TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036600.7
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), … (more)
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al. (1984). Orkin et al. (1982) reported the complete nucleotide sequence of a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the only abnormality. Expression of the beta-E gene was tested by introducing it into HeLa cells. Two abnormalities of RNA processing were shown: slow excision of intervening sequence-1 and alternative splicing into exon 1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. Antonarakis et al. (1982) used the Kazazian haplotype approach of analyzing DNA polymorphisms in the beta-globin cluster to present evidence that the beta-E mutation occurred at least twice in Southeast Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could be recognized by the restriction enzyme MnlI which cleaves DNA at the sequence 3-prime-GGAG-5-prime. Rey et al. (1991) described SE disease in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have increased risk of the complications of sickling including pneumococcal sepsis. Rees et al. (1996) reported a girl homozygous for Hb E with severe anemia and anisopoikilocytosis, who was also homozygous for pyrimidine 5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient for P5N, the stability of the Hb E was decreased. Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et al. (2002) examined the possible protective role of Hb E and other prevalent inherited hemoglobin abnormalities against malaria (611162) in Thailand. They assessed the effect of Hb E by means of a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin red blood cells, including those heterozygous and homozygous for Hb E. The heterozygote HbAE cells differed markedly from all the other cells tested, with invasion restricted to approximately 25% of the red blood cells. Despite their microcytosis, AE heterozygous cells were functionally relatively normal in contrast to the red blood cells from the other hemoglobinopathies studied. Chotivanich et al. (2002) interpreted these findings as suggesting that HbAE erythrocytes have an unidentified membrane abnormality that renders most of the red blood cell population relatively resistant to invasion by P. falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and was considered consistent with the 'Haldane hypothesis' of heterozygote protection against severe malaria for Hb E. The Hb E variant is concentrated in parts of Southeast Asia where malaria is endemic, and Hb E carrier status confers some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed biallelic markers surrounding the Hb E variant in a Thai population. Pairwise LD analysis of Hb E and 43 surrounding biallelic markers revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed between non-Hb E variants and the same markers. The inferred haplotype network suggested a single origin of the Hb E variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicated that the Hb E variant arose 1,240 to 4,440 years ago. Thus, the Hb E mutation occurred recently and allele frequency increased rapidly. The study demonstrated that a high resolution LD map across the human genome can detect recent variants that have been subjected to positive selection. The highest frequencies of the Hb E gene in large population samples, approximately 0.3, had been observed in the southern part of northeastern Thailand. Even higher frequencies were observed by Flatz et al. (2004) in Austroasiatic populations in southern Laos. One frequency was as high as 0.433 in a population of Sekong Province. As in other areas of Southeast Asia, hemoglobin E is a very common hemoglobin variant in India, where the highest prevalence of hemoglobin E has been observed in the northeastern regions. In West Bengal, carrier frequency varies from 5 to 35% in different subpopulations, whereas in Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%. Individuals heterozygous for hemoglobin E have normal or near-normal mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in peripheral blood. Homozygosity for hemoglobin E is commonly benign, characterized by mild hypochromic microcytic anemia with the presence of target cells. Edison et al. (2005) observed hyperbilirubinemia among patients with homozygosity for the hemoglobin E gene in the Indian population, with jaundice being the major complaint at presentation. A study of UGT1A1 gene polymorphism showed that the variant TA(7) in the promoter region of the UGT1A1 gene (191740.0011) was associated with hyperbilirubinemia in homozygous HbE patients. The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by P. falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. The estimated number of worldwide annual births of patients with HbE beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall, 2010). (less)
|
|
other
(Nov 03, 2009)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN E
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036597.9
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), … (more)
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al. (1984). Orkin et al. (1982) reported the complete nucleotide sequence of a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the only abnormality. Expression of the beta-E gene was tested by introducing it into HeLa cells. Two abnormalities of RNA processing were shown: slow excision of intervening sequence-1 and alternative splicing into exon 1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. Antonarakis et al. (1982) used the Kazazian haplotype approach of analyzing DNA polymorphisms in the beta-globin cluster to present evidence that the beta-E mutation occurred at least twice in Southeast Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could be recognized by the restriction enzyme MnlI which cleaves DNA at the sequence 3-prime-GGAG-5-prime. Rey et al. (1991) described SE disease in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have increased risk of the complications of sickling including pneumococcal sepsis. Rees et al. (1996) reported a girl homozygous for Hb E with severe anemia and anisopoikilocytosis, who was also homozygous for pyrimidine 5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient for P5N, the stability of the Hb E was decreased. Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et al. (2002) examined the possible protective role of Hb E and other prevalent inherited hemoglobin abnormalities against malaria (611162) in Thailand. They assessed the effect of Hb E by means of a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin red blood cells, including those heterozygous and homozygous for Hb E. The heterozygote HbAE cells differed markedly from all the other cells tested, with invasion restricted to approximately 25% of the red blood cells. Despite their microcytosis, AE heterozygous cells were functionally relatively normal in contrast to the red blood cells from the other hemoglobinopathies studied. Chotivanich et al. (2002) interpreted these findings as suggesting that HbAE erythrocytes have an unidentified membrane abnormality that renders most of the red blood cell population relatively resistant to invasion by P. falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and was considered consistent with the 'Haldane hypothesis' of heterozygote protection against severe malaria for Hb E. The Hb E variant is concentrated in parts of Southeast Asia where malaria is endemic, and Hb E carrier status confers some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed biallelic markers surrounding the Hb E variant in a Thai population. Pairwise LD analysis of Hb E and 43 surrounding biallelic markers revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed between non-Hb E variants and the same markers. The inferred haplotype network suggested a single origin of the Hb E variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicated that the Hb E variant arose 1,240 to 4,440 years ago. Thus, the Hb E mutation occurred recently and allele frequency increased rapidly. The study demonstrated that a high resolution LD map across the human genome can detect recent variants that have been subjected to positive selection. The highest frequencies of the Hb E gene in large population samples, approximately 0.3, had been observed in the southern part of northeastern Thailand. Even higher frequencies were observed by Flatz et al. (2004) in Austroasiatic populations in southern Laos. One frequency was as high as 0.433 in a population of Sekong Province. As in other areas of Southeast Asia, hemoglobin E is a very common hemoglobin variant in India, where the highest prevalence of hemoglobin E has been observed in the northeastern regions. In West Bengal, carrier frequency varies from 5 to 35% in different subpopulations, whereas in Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%. Individuals heterozygous for hemoglobin E have normal or near-normal mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in peripheral blood. Homozygosity for hemoglobin E is commonly benign, characterized by mild hypochromic microcytic anemia with the presence of target cells. Edison et al. (2005) observed hyperbilirubinemia among patients with homozygosity for the hemoglobin E gene in the Indian population, with jaundice being the major complaint at presentation. A study of UGT1A1 gene polymorphism showed that the variant TA(7) in the promoter region of the UGT1A1 gene (191740.0011) was associated with hyperbilirubinemia in homozygous HbE patients. The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by P. falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. The estimated number of worldwide annual births of patients with HbE beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall, 2010). (less)
|
|
Pathogenic
(Nov 03, 2009)
|
no assertion criteria provided
Method: literature only
|
BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036598.7
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), … (more)
This mutation is a cause of beta-plus-thalassemia (613985). See Hunt and Ingram (1961), Shibata et al. (1962), Blackwell et al. (1970), Fairbanks et al. (1980), Benz et al. (1981), and Kazazian et al. (1984). Orkin et al. (1982) reported the complete nucleotide sequence of a beta-E-globin gene. They found a GAG-to-AAG change in codon 26 as the only abnormality. Expression of the beta-E gene was tested by introducing it into HeLa cells. Two abnormalities of RNA processing were shown: slow excision of intervening sequence-1 and alternative splicing into exon 1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. Antonarakis et al. (1982) used the Kazazian haplotype approach of analyzing DNA polymorphisms in the beta-globin cluster to present evidence that the beta-E mutation occurred at least twice in Southeast Asia. Thein et al. (1987) demonstrated that the GAG-to-AAG change could be recognized by the restriction enzyme MnlI which cleaves DNA at the sequence 3-prime-GGAG-5-prime. Rey et al. (1991) described SE disease in 3 black American children of Haitian origin. They pointed out that the disorder is probably more benign than SC disease, SO(Arab) disease, and SC(Harlem) disease, all of which have increased risk of the complications of sickling including pneumococcal sepsis. Rees et al. (1996) reported a girl homozygous for Hb E with severe anemia and anisopoikilocytosis, who was also homozygous for pyrimidine 5-prime nucleotidase deficiency (P5N; 266120). In erythrocytes deficient for P5N, the stability of the Hb E was decreased. Hemoglobin E is very common in parts of Southeast Asia. Chotivanich et al. (2002) examined the possible protective role of Hb E and other prevalent inherited hemoglobin abnormalities against malaria (611162) in Thailand. They assessed the effect of Hb E by means of a mixed erythrocyte invasion assay. In vitro, starting at 1% parasitemia, Plasmodium falciparum preferentially invaded normal (HbAA) compared to abnormal hemoglobin red blood cells, including those heterozygous and homozygous for Hb E. The heterozygote HbAE cells differed markedly from all the other cells tested, with invasion restricted to approximately 25% of the red blood cells. Despite their microcytosis, AE heterozygous cells were functionally relatively normal in contrast to the red blood cells from the other hemoglobinopathies studied. Chotivanich et al. (2002) interpreted these findings as suggesting that HbAE erythrocytes have an unidentified membrane abnormality that renders most of the red blood cell population relatively resistant to invasion by P. falciparum. This would not protect from uncomplicated malaria infections but would prevent the development of heavy parasite burdens and was considered consistent with the 'Haldane hypothesis' of heterozygote protection against severe malaria for Hb E. The Hb E variant is concentrated in parts of Southeast Asia where malaria is endemic, and Hb E carrier status confers some protection against Plasmodium falciparum malaria. To examine the effect of natural selection on the pattern of linkage disequilibrium (LD) and to infer the evolutionary history of the Hb E variant, Ohashi et al. (2004) analyzed biallelic markers surrounding the Hb E variant in a Thai population. Pairwise LD analysis of Hb E and 43 surrounding biallelic markers revealed LD of Hb E extending beyond 100 kb, whereas no LD was observed between non-Hb E variants and the same markers. The inferred haplotype network suggested a single origin of the Hb E variant in the Thai population. Forward-in-time computer simulations under a variety of selection models indicated that the Hb E variant arose 1,240 to 4,440 years ago. Thus, the Hb E mutation occurred recently and allele frequency increased rapidly. The study demonstrated that a high resolution LD map across the human genome can detect recent variants that have been subjected to positive selection. The highest frequencies of the Hb E gene in large population samples, approximately 0.3, had been observed in the southern part of northeastern Thailand. Even higher frequencies were observed by Flatz et al. (2004) in Austroasiatic populations in southern Laos. One frequency was as high as 0.433 in a population of Sekong Province. As in other areas of Southeast Asia, hemoglobin E is a very common hemoglobin variant in India, where the highest prevalence of hemoglobin E has been observed in the northeastern regions. In West Bengal, carrier frequency varies from 5 to 35% in different subpopulations, whereas in Assam and Meghalaya, the heterozygous frequency ranges from 27 to 51%. Individuals heterozygous for hemoglobin E have normal or near-normal mean corpuscular volume (MCV) with 27 to 31% of the abnormal Hb in peripheral blood. Homozygosity for hemoglobin E is commonly benign, characterized by mild hypochromic microcytic anemia with the presence of target cells. Edison et al. (2005) observed hyperbilirubinemia among patients with homozygosity for the hemoglobin E gene in the Indian population, with jaundice being the major complaint at presentation. A study of UGT1A1 gene polymorphism showed that the variant TA(7) in the promoter region of the UGT1A1 gene (191740.0011) was associated with hyperbilirubinemia in homozygous HbE patients. The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage. O'Donnell et al. (2009) studied Sri Lankan patients with HbE beta-thalassemia for exposure to malaria caused by P. falciparum or P. vivax. They found that there were high frequencies of antibodies to both malaria parasites, as well as DNA-based evidence of current infection with P. vivax. Comparisons with age-matched controls showed that there was a higher frequency of antibodies in thalassemic patients, particularly against P. vivax and in young children, that was unlikely to be related to transfusion. A higher frequency was also found in patients who had undergone splenectomy. O'Donnell et al. (2009) proposed that patients with HbE beta-thalassemia may be more prone to malaria, particularly P. vivax malaria. The estimated number of worldwide annual births of patients with HbE beta-thalassemia is 19,128 (Modell and Darlison, 2008 and Weatherall, 2010). (less)
|
|
Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244657.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
Pathogenic
(May 07, 2024)
|
no assertion criteria provided
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
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MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN
Accession: SCV005186155.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The HBB variant c.79G>A (beta+), which results in unstable Hemoglobin E, is clinically benign when present in compound heterozygous with other Beta zero mutation. Accrpdingly … (more)
The HBB variant c.79G>A (beta+), which results in unstable Hemoglobin E, is clinically benign when present in compound heterozygous with other Beta zero mutation. Accrpdingly when this variant occurs alongside other pathogenic HBB variants, it can lead to varying degrees of anemia. The frequency of this variant varies across different populations in India.The prevalence of this variant shows significant regional differences. In the Bengali population of Eastern India, the prevalence is notably high at approximately 33.23%, whereas in the Northern Indian population, the frequency is very low, at around 0.2% among thalassemia patients. According to our multicentric Multicentric Project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations", Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018], (less)
Number of individuals with the variant: 334
Sex: mixed
Ethnicity/Population group: Southeast Asian
Geographic origin: India
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not provided
(-)
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no classification provided
Method: literature only
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Hb SS disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000190690.3
First in ClinVar: Dec 21, 2015 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Beta-Thalassemia. | Adam MP | - | 2024 | PMID: 20301599 |
Sickle Cell Disease. | Adam MP | - | 2023 | PMID: 20301551 |
Cross-Sectional Study for the Detection of Mutations in the Beta-Globin Gene Among Patients with Hemoglobinopathies in the Bengali Population. | Panja A | Genetic testing and molecular biomarkers | 2017 | PMID: 27828729 |
Clinical, Hematological and Molecular Analysis of Homozygous Hb E (HBB: c.79G > A) in the Indian Population. | Jayasree D | Hemoglobin | 2016 | PMID: 26554862 |
Molecular characterization of a β-thalassemia intermedia patient presenting inferior vena cava thrombosis: interaction of the β-globin erythroid Krüppel-like factor binding site mutation with Hb E and α(+)-thalassemia. | Prajantasen T | Hemoglobin | 2014 | PMID: 25370867 |
Variability of hemoglobin F expression in hemoglobin EE disease: hematological and molecular analysis. | Pakdee N | Blood cells, molecules & diseases | 2014 | PMID: 24581976 |
Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. | Nguyen VH | Blood cells, molecules & diseases | 2014 | PMID: 24368026 |
A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress. | Chen Q | Blood cells, molecules & diseases | 2012 | PMID: 22260787 |
In silico analysis of single nucleotide polymorphism (SNPs) in human β-globin gene. | Alanazi M | PloS one | 2011 | PMID: 22028795 |
Molecular analysis of globin gene expression in different thalassaemia disorders: individual variation of β(E) pre-mRNA splicing determine disease severity. | Tubsuwan A | British journal of haematology | 2011 | PMID: 21732929 |
Interaction of malaria with a common form of severe thalassemia in an Asian population. | O'Donnell A | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19841268 |
Global epidemiology of haemoglobin disorders and derived service indicators. | Modell B | Bulletin of the World Health Organization | 2008 | PMID: 18568278 |
Hemoglobin e syndromes. | Vichinsky E | Hematology. American Society of Hematology. Education Program | 2007 | PMID: 18024613 |
Hemoglobin SE disease: a concise review. | Masiello D | American journal of hematology | 2007 | PMID: 17278112 |
Thalassemia and hemoglobinopathies rather than iron deficiency are major causes of pregnancy-related anemia in northeast Thailand. | Sanchaisuriya K | Blood cells, molecules & diseases | 2006 | PMID: 16750922 |
Hyperbilirubinemia in homozygous HbE disease is associated with the UGT1A1 gene polymorphism. | Edison ES | Hemoglobin | 2005 | PMID: 16114182 |
The 'hot-spot' of Hb E [beta26(B8)Glu-->Lys] in Southeast Asia: beta-globin anomalies in the Lao Theung population of southern Laos. | Flatz G | Hemoglobin | 2004 | PMID: 15481886 |
Genotypes and phenotypes--another lesson from the hemoglobinopathies. | Benz EJ Jr | The New England journal of medicine | 2004 | PMID: 15470211 |
Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection. | Ohashi J | American journal of human genetics | 2004 | PMID: 15114532 |
The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. | Premawardhena A | Blood cells, molecules & diseases | 2003 | PMID: 12850492 |
Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria. | Chotivanich K | Blood | 2002 | PMID: 12149194 |
Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. | Premawardhena A | Lancet (London, England) | 2001 | PMID: 11425418 |
Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? | Beutler E | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9653159 |
Interaction of hemoglobin E and pyrimidine 5' nucleotidase deficiency. | Rees DC | Blood | 1996 | PMID: 8839873 |
Sickle cell-hemoglobin E disease: clinical findings and implications. | Rey KS | The Journal of pediatrics | 1991 | PMID: 1960615 |
Direct detection of haemoglobin E with MnlI. | Thein SL | Journal of medical genetics | 1987 | PMID: 3031297 |
Hemoglobin E in Europeans: further evidence for multiple origins of the beta E-globin gene. | Kazazian HH Jr | American journal of human genetics | 1984 | PMID: 6198908 |
Abnormal RNA processing due to the exon mutation of beta E-globin gene. | Orkin SH | Nature | 1982 | PMID: 7177196 |
Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. | Orkin SH | Nature | 1982 | PMID: 6280057 |
Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster. | Antonarakis SE | Proceedings of the National Academy of Sciences of the United States of America | 1982 | PMID: 6275383 |
Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys). | Benz EJ Jr | The Journal of clinical investigation | 1981 | PMID: 6166632 |
Homozygous hemoglobin E mimics beta-thalassemia minor without anemia or hemolysis: hematologic, functional, and biosynthetic studies of first North American cases. | Fairbanks VF | American journal of hematology | 1980 | PMID: 7395858 |
A genetically determined disorder with features both of thalassaemia and congenital dyserythropoietic anaemia. | Weatherall DJ | British journal of haematology | 1973 | PMID: 4351905 |
Hemoglobin variant common to Chinese and North American Indians: alpha-2-beta-22 Glu-Ala. | Blackwell RW | Science (New York, N.Y.) | 1968 | PMID: 5658717 |
Haemoglobin E and beta-thalassaemia: their distribution in Thailand. | Flatz G | Annals of human genetics | 1965 | PMID: 5863839 |
SPECTROPHOTOMETRIC DETERMINATION OF HB M-IWATE IN THE HEMOLYSATE OF HEREDITARY NIGREMIA. | SHIBATA S | The Bulletin of the Yamaguchi Medical School | 1963 | PMID: 14091853 |
Abnormal human haemoglobins. VI. The chemical difference between haemoglobins A and E. | HUNT JA | Biochimica et biophysica acta | 1961 | PMID: 13716853 |
https://ithanet.eu/db/ithagenes?ithaID=88 | - | - | - | - |
Kazazian, H. H., Jr. Personal Communication. 1992. Baltimore, Md. | - | - | - | - |
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Text-mined citations for rs33950507 ...
HelpRecord last updated Sep 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.