Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 143240 control chromosomes, predominantly at a frequency of 0.00017 within the African or African-American subpopulation in the gnomAD database (v3 genome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.220G>A is also known as Hb G-Accra or Hb Korle-Bu when found in isolation, and as Hb C-Harlem or Hb C-Georgetown when found in cis with the Hb S mutation. When present in homozygosity, this variant reportedly does not cause hemoglobinopathy, and is considered an unusual hemoglobin rather than an abnormal/harmful hemoglobin (Boi-Doku_1964, Konotey_1968). In compound heterozygosity with HbS, HbC or beta-thal mutations, the variant of interest reportedly causes no apparent sickness and leads to a sickle-cell trait (when in compound heterozygosity with HbS) rather than sickle-cell disease, HbC disease or beta thalassemia, and does not seem to aggravate the mild status of beta thalassemia heterozygosity (Akl_2009, Chico_2004, Huisman_1997, Konotey_1968, van der Padt_2005). Three publications reported experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect (Bookchin_1967, Nagel_1993, Ivanova_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_000518.4(HBB):c.220G>A (p.Asp74Asn)
Germline
Classification
Help
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.
(6)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Likely benign(3)
Uncertain significance(1); Likely benign(3)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_000518.4(HBB):c.220G>A (p.Asp74Asn)
Variation ID: 15244 Accession: VCV000015244.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 5226672 (GRCh38) [ NCBI UCSC ] 11: 5247902 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Mar 17, 2018 Feb 20, 2024 Nov 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.220G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Asp74Asn missense NC_000011.10:g.5226672C>T NC_000011.9:g.5247902C>T NG_000007.3:g.70944G>A NG_042296.1:g.203C>T NG_046672.1:g.4607C>T NG_053049.1:g.2993C>T NG_059281.1:g.5400G>A LRG_1232:g.5400G>A LRG_1232t1:c.220G>A LRG_1232p1:p.Asp74Asn - Protein change
- D74N
- Other names
-
D73N
- Canonical SPDI
- NC_000011.10:5226671:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00005
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1834 | |
| LOC106099062 | - | - | - | GRCh38 | - | 862 |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
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. |
|---|---|---|---|---|
|
HEMOGLOBIN KORLE-BU
|
other (1) |
no assertion criteria provided
|
Dec 12, 2017 | RCV000016449.12 |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Nov 27, 2023 | RCV000587238.23 | |
| Likely benign (1) |
criteria provided, single submitter
|
Aug 7, 2020 | RCV000855647.12 | |
| Likely benign (1) |
no assertion criteria provided
|
Jan 22, 2021 | RCV001826465.9 |
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(Aug 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697095.3
First in ClinVar: Mar 17, 2018 Last updated: Sep 14, 2020 |
Comment:
Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 143240 control chromosomes, predominantly at a frequency of 0.00017 within the African or African-American subpopulation in the gnomAD database (v3 genome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.220G>A is also known as Hb G-Accra or Hb Korle-Bu when found in isolation, and as Hb C-Harlem or Hb C-Georgetown when found in cis with the Hb S mutation. When present in homozygosity, this variant reportedly does not cause hemoglobinopathy, and is considered an unusual hemoglobin rather than an abnormal/harmful hemoglobin (Boi-Doku_1964, Konotey_1968). In compound heterozygosity with HbS, HbC or beta-thal mutations, the variant of interest reportedly causes no apparent sickness and leads to a sickle-cell trait (when in compound heterozygosity with HbS) rather than sickle-cell disease, HbC disease or beta thalassemia, and does not seem to aggravate the mild status of beta thalassemia heterozygosity (Akl_2009, Chico_2004, Huisman_1997, Konotey_1968, van der Padt_2005). Three publications reported experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect (Bookchin_1967, Nagel_1993, Ivanova_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Likely benign
(Apr 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134215.5
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
|
|
|
Uncertain significance
(Feb 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235257.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603915.6
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
|
|
|
other
(Dec 12, 2017)
|
no assertion criteria provided
Method: literature only
|
HEMOGLOBIN KORLE-BU
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036717.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
Since this same substitution is present with the sickle hemoglobin change as one of the two defects in hemoglobin C(Harlem), Konotey-Ahulu et al. (1968) suggested … (more)
Since this same substitution is present with the sickle hemoglobin change as one of the two defects in hemoglobin C(Harlem), Konotey-Ahulu et al. (1968) suggested that the latter hemoglobin may have arisen by intracistronic crossing-over in an individual with the Korle-Bu gene on one chromosome and the sickle gene on the other. See Konotey-Ahulu et al. (1968) and Honig et al. (1983). Nagel et al. (1993) showed that compound heterozygosity for hemoglobin Korle-Bu (HbKB) and HbC (141900.0038) is associated with moderate chronic hemolytic anemia with microcytosis. They found that in vitro hemoglobin crystals formed within 2 minutes compared with 30 minutes for a mixture of 40% HbC and 60% HbS and within 180 minutes for 40% HbC with 60% HbA. The crystals were cubic in contrast with the tetragonal crystals observed in CC and SC disease. They concluded that the hemolysis observed in the HbKB/C compound heterozygote is likely to be secondary to the acceleration of Hb crystallization. (less)
|
|
|
Likely benign
(Jan 22, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089212.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
Comment:
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. |
Comment:
Variant summary: HBB c.220G>A (p.Asp74Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 143240 control chromosomes, predominantly at a frequency of 0.00017 within the African or African-American subpopulation in the gnomAD database (v3 genome dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.220G>A is also known as Hb G-Accra or Hb Korle-Bu when found in isolation, and as Hb C-Harlem or Hb C-Georgetown when found in cis with the Hb S mutation. When present in homozygosity, this variant reportedly does not cause hemoglobinopathy, and is considered an unusual hemoglobin rather than an abnormal/harmful hemoglobin (Boi-Doku_1964, Konotey_1968). In compound heterozygosity with HbS, HbC or beta-thal mutations, the variant of interest reportedly causes no apparent sickness and leads to a sickle-cell trait (when in compound heterozygosity with HbS) rather than sickle-cell disease, HbC disease or beta thalassemia, and does not seem to aggravate the mild status of beta thalassemia heterozygosity (Akl_2009, Chico_2004, Huisman_1997, Konotey_1968, van der Padt_2005). Three publications reported experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect (Bookchin_1967, Nagel_1993, Ivanova_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and both of them classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Curating the gnomAD database: Report of novel variants in the globin-coding genes and bioinformatics analysis. | Scheps KG | Human mutation | 2020 | PMID: 31553106 |
| Compound Heterozygosity for Hb D-Ibadan (HBB: c.263C>A) and Hb C (HBB: c.19G>A). | Kundrapu S | Hemoglobin | 2018 | PMID: 30604644 |
| Clinical, hematological and genetic data of a cohort of children with hemoglobin SD. | Rezende Pdo V | Revista brasileira de hematologia e hemoterapia | 2016 | PMID: 27521862 |
| Comments on: "Clinical, hematological and genetic data of a cohort of children with hemoglobin SD". | Figueiredo MS | Revista brasileira de hematologia e hemoterapia | 2016 | PMID: 27521855 |
| Hemoglobin Variants in Northern Thailand: Prevalence, Heterogeneity and Molecular Characteristics. | Panyasai S | Genetic testing and molecular biomarkers | 2016 | PMID: 26544676 |
| Newborn Screening for Sickle Cell Disease: Jamaican Experience. | Mason K | The West Indian medical journal | 2015 | PMID: 26901597 |
| Detection of sickle cell hemoglobin in Haiti by genotyping and hemoglobin solubility tests. | Carter TE | The American journal of tropical medicine and hygiene | 2014 | PMID: 24957539 |
| Hb S-São Paulo: a new sickling hemoglobin with stable polymers and decreased oxygen affinity. | Jorge SE | Archives of biochemistry and biophysics | 2012 | PMID: 22244832 |
| Renal medullary carcinomas: histopathologic phenotype associated with diverse genotypes. | Gatalica Z | Human pathology | 2011 | PMID: 21733559 |
| Complex interaction of Hb E [beta26(B8)Glu-->Lys], Hb Korle-Bu [beta73(E17)Asp-->Asn] and a deletional alpha-thalassemia-1 in pregnancy. | Siriratmanawong N | Hemoglobin | 2009 | PMID: 19958198 |
| Compound heterozygosity for hemoglobin S [beta6(A3)Glu6Val] and hemoglobin Korle-Bu [beta73(E17)Asp73Asn]. | Akl PS | Laboratory hematology : official publication of the International Society for Laboratory Hematology | 2009 | PMID: 19758965 |
| Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
| Adult onset of a Thalassemia intermedia genotype in association with a -alpha-3.7 homozygosity. Hb G-Accra [beta73(e17)Asp-->Asn] in combination with beta- and alpha-thalassemia in the same family. | van der Padt A | Hemoglobin | 2005 | PMID: 16370487 |
| A novel sickle hemoglobin: hemoglobin S-south end. | Luo HY | Journal of pediatric hematology/oncology | 2004 | PMID: 15543018 |
| The Korle-Bu Hb variant in Caucasian women with type 1 diabetes: a pitfall in the assessment of diabetes control. | Chico A | Diabetes care | 2004 | PMID: 15333505 |
| Flexibility and nucleation in sickle hemoglobin. | Ivanova M | Journal of molecular biology | 2001 | PMID: 11734002 |
| 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 |
| Hemoglobin Korle-Bu (G-ACCRA) in combination with hemoglobin C. | Vukelja SJ | American journal of hematology | 1993 | PMID: 8494004 |
| Compound heterozygosity for hemoglobin C and Korle-Bu: moderate microcytic hemolytic anemia and acceleration of crystal formation [corrected]. | Nagel RL | Blood | 1993 | PMID: 7691242 |
| A new doubly substituted sickling haemoglobin: HbS-Oman. | Langdown JV | British journal of haematology | 1989 | PMID: 2930724 |
| Hemoglobin Korle Bu in a Mexican family. | Honig GR | Hemoglobin | 1983 | PMID: 6671904 |
| The hemoglobin P-Galveston-Hb-C conduction in members of a black family from South Carolina. | Huisman TH | FEBS letters | 1978 | PMID: 700140 |
| Homozygous hemoglobin O Arab in a gypsy family in Yugoslavia. | Efremov GD | Hemoglobin | 1977 | PMID: 893136 |
| Abnormal hemoglobins in a quarter million people. | Schneider RG | Blood | 1976 | PMID: 974261 |
| The presence of hemoglobin S and C Harlem in an individual in the United States. | Moo-Penn W | Blood | 1975 | PMID: 1148394 |
| Haemoglobin Korle-Bu (beta 73 aspartic acid replaced by asparagine) showing one of the two amino acid substitutions of haemoglobin C Harlem. | Konotey-Ahulu FI | Journal of medical genetics | 1968 | PMID: 5722880 |
| Structure and properties of hemoglobin C-Harlem, a human hemoglobin variant with amino acid substitutions in 2 residues of the beta-polypeptide chain. | Bookchin RM | The Journal of biological chemistry | 1967 | PMID: 6016610 |
| High incidence of haemoglobin G Accra in a rural district in Jamaica. | Milner PF | Journal of medical genetics | 1967 | PMID: 5619995 |
| HAEMOGLOBIN GACCA. | BOI-DOKU FS | Nature | 1964 | PMID: 14197371 |
| Characterization and genetics of haemoglobin G. | EDINGTON GM | Nature | 1955 | PMID: 14370233 |
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Text-mined citations for rs33945705 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.