ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.20del (p.Glu7fs)
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.20del (p.Glu7fs)
Variation ID: 15418 Accession: VCV000015418.113
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5227002 (GRCh38) [ NCBI UCSC ] 11: 5248232 (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 Apr 20, 2024 Jan 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.20del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Glu7fs frameshift NM_000518.4:c.20del NC_000011.10:g.5227002del NC_000011.9:g.5248232del NG_000007.3:g.70614del NG_042296.1:g.533del NG_046672.1:g.4937del NG_059281.1:g.5070del LRG_1232:g.5070del LRG_1232t1:c.20del LRG_1232p1:p.Glu7fs - Protein change
- E7fs
- Other names
- CD 6 -A
- Canonical SPDI
- NC_000011.10:5227001: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1993 | RCV000016674.37 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2023 | RCV000576555.19 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 16, 2024 | RCV001008068.38 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004359.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2022 | RCV002496381.8 |
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
(Jul 20, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697093.1
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
Comment:
Variant summary: The HBB c.20delA (p.Glu7Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense … (more)
Variant summary: The HBB c.20delA (p.Glu7Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. In addition, this region is known to be a mutational hot-spot. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.27dupG, c.36delT, c.46delT, etc.). This variant was found in 3/121348 control chromosomes at a frequency of 0.0000247, which is lower than the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a known common pathogenic variant mainly reported in Algerian, Moroccan, and Sardinian populations in homozygous and/or heterozygous state. Additionally, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as a Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163296.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Jan 17, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002573740.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
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Pathogenic
(Apr 20, 2022)
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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-globin type Erythrocytosis, familial, 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811968.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 30, 2022)
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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: SCV001167805.3
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
Observed multiple times in published literature in individuals with Beta-Thalassemia; however detailed clinical information and segregation was not provided (Economou et al., 1991; Rosatelli et … (more)
Observed multiple times in published literature in individuals with Beta-Thalassemia; however detailed clinical information and segregation was not provided (Economou et al., 1991; Rosatelli et al., 1992; Baysal et al 1992; Gonzalez-Redondo et al., 1988; Kazazian et al., 1983); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27785405, 6310991, 9163586, 34662886, 22975760, 26956563, 1390250, 8262525, 1734721, 17486495, 2458145, 1769663) (less)
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Pathogenic
(Jan 16, 2024)
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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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Invitae
Accession: SCV001590406.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu7Glyfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu7Glyfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs63749819, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Œ=-thalassemia (PMID: 6310991). This variant is also known as deletion of A in codon 6 of the beta gene. ClinVar contains an entry for this variant (Variation ID: 15418). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 06, 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: SCV000603925.10
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The HBB c.20delA; p.Glu7fs variant (also known as Glu6fs when numbered from the mature protein or as Codon 6 (-A), rs63749819, HbVar ID: 784) has … (more)
The HBB c.20delA; p.Glu7fs variant (also known as Glu6fs when numbered from the mature protein or as Codon 6 (-A), rs63749819, HbVar ID: 784) has been reported in multiple individuals with beta(0) thalassemia (Bouhass 1990, Gonzalez-Redondo 1988, Kazazian 1983, Rosatelli 1992, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.002% (4/251184 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database for Codon 6 (-A): https://globin.bx.psu.edu/hbvar/hbvar.html Bouhass R et al. A new mutation at IVS1 nt 2(T----A), in beta-thalassemia from Algeria. Blood. 1990; 76(5):1054-5. PMID: 2393712. Kazazian HH Jr et al. beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene. Am J Hum Genet. 1983; 35(5):1028-33. PMID: 6310991. Gonzalez-Redondo J et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. PMID: 2458145. Rosatelli M et al. Molecular characterization of beta-thalassemia in the Sardinian population. Am J Hum Genet. 1992; 50(2):422-6. PMID: 1734721. (less)
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847533.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Glu7GlyfsX13 variant in HBB has been reported in >20 compound heterozygous or homozygous individuals with beta-thalassemia (Chang 1983 PMID: 6316272, Kazazian 1983 PMID: 6310991, … (more)
The p.Glu7GlyfsX13 variant in HBB has been reported in >20 compound heterozygous or homozygous individuals with beta-thalassemia (Chang 1983 PMID: 6316272, Kazazian 1983 PMID: 6310991, Gonzalez-Redondo 1988 PMID: 2458145, Bouhass 1990 PMID: 2393712, Petkov 1990 PMID: 2200762, Economou 1991 PMID: 1769663, Baysal 1992 PMID: 1390250, Rosatelli 1992 PMID: 1734721, Vetter 1997 PMID: 9163586, Danjou 2012 PMID: 22271886). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 15418) and has been identified in 0.0048% (2/41456) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 7 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta-thalassemia. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting. (less)
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Pathogenic
(Dec 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193849.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000518.4(HBB):c.20delA(aka p.E7Gfs*13) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is a beta-zero variant associated with beta thalessemia. Sources cited … (more)
NM_000518.4(HBB):c.20delA(aka p.E7Gfs*13) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is a beta-zero variant associated with beta thalessemia. Sources cited for classification include the following: PMID 22271886 and 1734721. Classification of NM_000518.4(HBB):c.20delA(aka p.E7Gfs*13) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jan 01, 2022)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497101.12
First in ClinVar: Apr 11, 2022 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 1993)
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no assertion criteria provided
Method: literature only
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BETA-ZERO-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036944.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Frameshift, -A, codon 6, GAG to GG, was found in Mediterranean patients by Kazazian et al. (1983). Bouhass et al. (1990) found the same mutation … (more)
Frameshift, -A, codon 6, GAG to GG, was found in Mediterranean patients by Kazazian et al. (1983). Bouhass et al. (1990) found the same mutation in an Algerian patient who was a genetic compound. Rosatelli et al. (1992) found that this mutation accounted for 2.1% of mutations carried by 3,000 beta-thalassemia chromosomes from the Sardinian population. Romey et al. (1993) described an improved procedure that allows the detection of single basepair deletions on nondenaturing polyacrylamide gels and demonstrated its applicability for identifying this mutation. (less)
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Pathogenic
(Nov 25, 2019)
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no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244474.1
First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020 |
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Pathogenic
(Mar 17, 2017)
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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: SCV002091613.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002320682.2
First in ClinVar: Apr 02, 2022 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 |
The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion. | Danjou F | Haematologica | 2012 | PMID: 22271886 |
Beta-thalassaemia in the immigrant and non-immigrant German populations. | Vetter B | British journal of haematology | 1997 | PMID: 9163586 |
Rapid detection of single nucleotide deletions: application to the beta 6 (-A) mutation of the beta-globin gene and to cystic fibrosis. | Romey MC | Human genetics | 1993 | PMID: 8262525 |
Molecular characterization of beta-thalassemia in the Sardinian population. | Rosatelli MC | American journal of human genetics | 1992 | PMID: 1734721 |
The beta-thalassaemia mutations in the population of Cyprus. | Baysal E | British journal of haematology | 1992 | PMID: 1390250 |
Molecular heterogeneity of beta-thalassemia in mestizo Mexicans. | Economou EP | Genomics | 1991 | PMID: 1769663 |
A new mutation at IVS1 nt 2(T----A), in beta-thalassemia from Algeria. | Bouhass R | Blood | 1990 | PMID: 2393712 |
Beta-thalassemia in Bulgaria. | Petkov GH | Hemoglobin | 1990 | PMID: 2200762 |
Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. | Gonzalez-Redondo JM | Blood | 1988 | PMID: 2458145 |
A beta-thalassemia lesion abolishes the same Mst II site as the sickle mutation. | Chang JC | Nucleic acids research | 1983 | PMID: 6316272 |
beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene. | Kazazian HH Jr | American journal of human genetics | 1983 | PMID: 6310991 |
https://globin.bx.psu.edu/hbvar/menu.html | - | - | - | - |
https://ithanet.eu/db/ithagenes?ithaID=57 | - | - | - | - |
Kazazian, H. H., Jr. Personal Communication. 1990. Baltimore, Md. | - | - | - | - |
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Text-mined citations for rs63749819 ...
HelpRecord last updated Apr 20, 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.