ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.286A>G (p.Lys96Glu)
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.
Uncertain significance(1); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.286A>G (p.Lys96Glu)
Variation ID: 15278 Accession: VCV000015278.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226606 (GRCh38) [ NCBI UCSC ] 11: 5247836 (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 Sep 30, 2017 Feb 20, 2024 Oct 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.286A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Lys96Glu missense NC_000011.10:g.5226606T>C NC_000011.9:g.5247836T>C NG_000007.3:g.71010A>G NG_042296.1:g.137T>C NG_046672.1:g.4541T>C NG_053049.1:g.2927T>C NG_059281.1:g.5466A>G LRG_1232:g.5466A>G LRG_1232t1:c.286A>G LRG_1232p1:p.Lys96Glu - Protein change
- K96E
- Other names
- K95E
- Canonical SPDI
- NC_000011.10:5226605:T:C
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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 |
21 | 1815 | |
LOC106099062 | - | - | - | GRCh38 | - | 849 |
LOC107133510 | - | - | - | GRCh38 | - | 1767 |
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
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Dec 12, 2017 | RCV000016504.12 | |
other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016505.12 | |
other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016506.12 | |
other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016507.12 | |
other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016508.12 | |
Likely benign (1) |
no assertion criteria provided
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Sep 23, 2020 | RCV001835628.9 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 5, 2022 | RCV000506157.16 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 30, 2023 | RCV000755549.21 |
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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Likely benign
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601266.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
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Uncertain significance
(Jun 26, 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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Revvity Omics, Revvity
Accession: SCV004235258.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely benign
(Oct 30, 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: SCV000603949.6
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Oct 05, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917491.3
First in ClinVar: Jun 02, 2019 Last updated: Nov 19, 2022 |
Comment:
Variant summary: HBB c.286A>G (p.Lys96Glu) also known as Hb-N Baltimore, results in a conservative amino acid change located in the Globin domain of the encoded … (more)
Variant summary: HBB c.286A>G (p.Lys96Glu) also known as Hb-N Baltimore, results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277156 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Multiple publications cite the variant with in asymptomatic and mildly affected individuals with normal hematological parameters characteristic of alpha thal-trait (in settings of -alpha/-alpha genotype) or a beta-thal trait (in setting of Hb-N-Baltimore/beta-thal) (Johnson_1976, Adams_1977, Ballas_1985, Hirsch_1997, Huisman_1997). A case study by Farashi_2016 reports the variant to occur in cis with HBB c.272_295dup (a duplication of eight codons) in a mother and daughter with relatively normal hematological parameters, however, authors speculate that the variant of interest could also influence structural changes. Functional studies showed that this variant significantly accelerated the crystallization of HbC (Hirsch_1997), inhibited gelation of HbS in deoxy state while behaving like HbA in oxy state (Kumpati_1978) and was associated with normal oxygen affinity (Craescu_1988). Furthermore, the variant showed poor reducibility of oxidized hemoglobin and impairment in interaction with cytochrome b5 (Gacon_1980). However, the impact of these findings on the pathophysiology of hemoglobinopathies is unclear. This variant is widely regarded as an apparently harmless or a clinically benign hemoglobin in the literature spanning over 3 decades (example, Schneider_1976, Mason_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN N (JENKINS)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036773.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration … (more)
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration of Hb N (Baltimore) is the same as that of HbA. Hemoglobin Kenwood was previously reported incorrectly as having either aspartic acid or glutamic acid at beta 143. See personal communication from Heller in Hamilton et al. (1969). (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN N (BALTIMORE)
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036772.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration … (more)
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration of Hb N (Baltimore) is the same as that of HbA. Hemoglobin Kenwood was previously reported incorrectly as having either aspartic acid or glutamic acid at beta 143. See personal communication from Heller in Hamilton et al. (1969). (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN JENKINS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036774.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration … (more)
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration of Hb N (Baltimore) is the same as that of HbA. Hemoglobin Kenwood was previously reported incorrectly as having either aspartic acid or glutamic acid at beta 143. See personal communication from Heller in Hamilton et al. (1969). (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN KENWOOD
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036776.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration … (more)
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration of Hb N (Baltimore) is the same as that of HbA. Hemoglobin Kenwood was previously reported incorrectly as having either aspartic acid or glutamic acid at beta 143. See personal communication from Heller in Hamilton et al. (1969). (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN HOPKINS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036775.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration … (more)
See Clegg et al. (1965), Dobbs et al. (1966), Gottlieb et al. (1967), Ballas and Park (1985), and Anderson Fernandes (1989). In heterozygotes the concentration of Hb N (Baltimore) is the same as that of HbA. Hemoglobin Kenwood was previously reported incorrectly as having either aspartic acid or glutamic acid at beta 143. See personal communication from Heller in Hamilton et al. (1969). (less)
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Likely benign
(Sep 23, 2020)
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no assertion criteria provided
Method: clinical testing
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Beta thalassemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002089201.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 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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Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
Interaction between hemoglobin S and N-Baltimore: a case report in Pernambuco, Brazil. | Batista THC | Hematology, transfusion and cell therapy | 2019 | PMID: 31126755 |
Prevalence of Rare Hemoglobin Variants Identified During Measurements of Hb A(1c) by Capillary Electrophoresis. | Strickland SW | Clinical chemistry | 2017 | PMID: 28904057 |
Report on Ten Years' Experience of Premarital Hemoglobinopathy Screening at a Center in Antalya, Southern Turkey. | Canatan D | Hemoglobin | 2016 | PMID: 27207683 |
First Report of a Dominantly Inherited β-Thalassemia Caused by a Novel Elongated β-Globin Chain. | Farashi S | Hemoglobin | 2016 | PMID: 26850598 |
Newborn Screening for Sickle Cell Disease: Jamaican Experience. | Mason K | The West Indian medical journal | 2015 | PMID: 26901597 |
Effects of hemoglobin variants on hemoglobin a1c values measured using a high-performance liquid chromatography method. | Lorenzo-Medina M | Journal of diabetes science and technology | 2014 | PMID: 25355712 |
Distinctive mutation spectrum of the HBB gene in an urban eastern Indian population. | Sahoo SS | Hemoglobin | 2014 | PMID: 24099628 |
The accurate prediction of rare hemoglobin variants using a combination of high performance liquid chromatography, retention time and isoelectric focusing electrophoresis position. | Khalil MS | Saudi medical journal | 2009 | PMID: 19750260 |
A novel sickle hemoglobin: hemoglobin S-south end. | Luo HY | Journal of pediatric hematology/oncology | 2004 | PMID: 15543018 |
Combinations of beta chain abnormal hemoglobins with each other or with beta-thalassemia determinants with known mutations: influence on phenotype. | Huisman TH | Clinical chemistry | 1997 | PMID: 9342003 |
HbC compound heterozygotes [HbC/Hb Riyadh and HbC/Hb N-Baltimore] with opposing effects upon HbC crystallization. | Hirsch RE | British journal of haematology | 1997 | PMID: 9163585 |
Role of alpha and beta carboxyl-terminal residues in the kinetics of human oxyhemoglobin dimer assembly. | Joshi AA | The Journal of biological chemistry | 1994 | PMID: 7907594 |
Hb N-Baltimore [alpha 2 beta 2(95)(FG2)Lys----Glu] and Hb J-Iran [alpha 2 beta 2(77)(Ef1]His----Asp] observed in a Turkish family from Antalya. | Bircan I | Hemoglobin | 1990 | PMID: 2283300 |
Proton NMR studies of human hemoglobin variants modified in the proximal side of beta heme pocket. Implications for the affinity control and cooperative mechanism. | Craescu CT | The Journal of biological chemistry | 1988 | PMID: 3343245 |
Electrostatic attraction governs the dimer assembly of human hemoglobin. | Mrabet NT | The Journal of biological chemistry | 1986 | PMID: 3957922 |
Biosynthetic evidence for stability of Hb N-Baltimore. | Ballas SK | Hemoglobin | 1985 | PMID: 4086303 |
Percentages of abnormal hemoglobins in adults with a heterozygosity for an alpha-chain and/or a beta-chain variant. | Huisman TH | American journal of hematology | 1983 | PMID: 6859036 |
Interaction between cytochrome b5 and hemoglobin: involvement of beta 66 (E10) and beta 95 (FG2) lysyl residues of hemoglobin. | Gacon G | Proceedings of the National Academy of Sciences of the United States of America | 1980 | PMID: 6769116 |
The hemoglobin P-Galveston-Hb-C conduction in members of a black family from South Carolina. | Huisman TH | FEBS letters | 1978 | PMID: 700140 |
Interaction between human hemoglobin variants and hemoglobin S. | Kumpati J | Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) | 1978 | PMID: 622390 |
Hemoglobin Arlington Park. A new hemoglobin variant with two amino acid substitutions in the beta chain. | Adams JG | Hemoglobin | 1977 | PMID: 893139 |
Hemoglobin St. Louis [beta 28 (B10) Leu replaced by Gln]: crystal structure of the fully reduced (deoxy) form. | Anderson NL | The Journal of clinical investigation | 1976 | PMID: 993333 |
Abnormal hemoglobins in a quarter million people. | Schneider RG | Blood | 1976 | PMID: 974261 |
A case with both hemoglobins C and N-Baltimore. | Johnson C | Acta haematologica | 1976 | PMID: 826073 |
Hemoglobin Hiroshima (beta-143 histidine--aspartic acid): a newly identified fast moving beta chain variant associated with increased oxygen affinity and compensatory erythremia. | Hamilton HB | The Journal of clinical investigation | 1969 | PMID: 5773089 |
Primary structure of Hopkins-1 haemoglobin. | Gottlieb AJ | Nature | 1967 | PMID: 6034218 |
Hemoglobin Jenkins or hemoglobin-N-Baltimore or alpha-2-beta-2 95Glu. | Dobbs NB Jr | Biochimica et biophysica acta | 1966 | PMID: 5961314 |
An improved method for the characterization of human haemoglobin mutants: identification of alpha-2-beta-2-95GLU, haemoglobin N (Baltimore). | Clegg JB | Nature | 1965 | PMID: 5886928 |
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Text-mined citations for rs33914359 ...
HelpRecord last updated May 01, 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.