ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.217dup (p.Ser73fs)
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.217dup (p.Ser73fs)
Variation ID: 15419 Accession: VCV000015419.115
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226674-5226675 (GRCh38) [ NCBI UCSC ] 11: 5247904-5247905 (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 May 1, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.217dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Ser73fs frameshift NM_000518.4:c.217dupA NC_000011.10:g.5226675dup NC_000011.9:g.5247905dup NG_000007.3:g.70940_70941insA NG_000007.3:g.70941dup NG_042296.1:g.206dup NG_046672.1:g.4610dup NG_053049.1:g.2996dup NG_059281.1:g.5397dup LRG_1232:g.5397dup LRG_1232t1:c.217dup LRG_1232p1:p.Ser73fs - Protein change
- S73fs
- Other names
- CD 71/72 (+A)
- Canonical SPDI
- NC_000011.10:5226674:T:TT
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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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
20 | 1819 | |
LOC106099062 | - | - | - | GRCh38 | - | 853 |
LOC107133510 | - | - | - | GRCh38 | - | 1772 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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May 1, 1984 | RCV000016675.37 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2019 | RCV000576855.17 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000507557.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2016 | RCV002426508.9 |
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
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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
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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
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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 pathogenic
(Dec 20, 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: SCV001193879.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that S73Kfs*2 is associated with beta thalassemia and … (more)
NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that S73Kfs*2 is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6585831. Classification of NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) 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 observed in an individual with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Dec 30, 2020)
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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: SCV000601259.5
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The HBB c.217dup (p.Ser73Lysfs*2) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This … (more)
The HBB c.217dup (p.Ser73Lysfs*2) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 26956563 (2016), 24369358 (2014), 6585831 (1984)). (less)
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Pathogenic
(Jan 04, 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: SCV001410459.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser73Lysfs*2) 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.Ser73Lysfs*2) 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 (rs606231217, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 6585831). This variant is also known as c.216_217insA or as an insertion of an A nucleotide between codons 71 and 72. ClinVar contains an entry for this variant (Variation ID: 15419). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 15, 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: SCV000697094.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The HBB c.217dupA (p.Ser73Lysfs) 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.217dupA (p.Ser73Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gly84fs). One in silico tool predicts a damaging outcome for this variant. Additionally, Cheng_PNAS_1984 reported the absence of beta-globin RNA in erythroid cells of a patient homozygous for this variant. The variant was reported in multiple unrelated BTHAL patients in the literature, and authors all classified the variant as pathogenic. This variant was found in 1/121394 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Sep 06, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002058086.3
First in ClinVar: Jan 15, 2022 Last updated: Mar 04, 2023 |
Comment:
The HBB c.217dupA; p.Ser73LysfsTer2 variant (also known as Ser72fs when numbered from the mature protein or as codon 71/72 (+A); HbVar ID: 869) has been … (more)
The HBB c.217dupA; p.Ser73LysfsTer2 variant (also known as Ser72fs when numbered from the mature protein or as codon 71/72 (+A); HbVar ID: 869) has been reported in individuals with beta(0) thalassemia, including in a homozygous individual with no detectable HBB mRNA (see HbVar, Cheng 1984). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.217dupA variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984; 81(9):2821-5. PMID: 6585831. (less)
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Pathogenic
(Sep 02, 2016)
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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: SCV002727311.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.217dupA pathogenic mutation (also known as codons 71/72 insertion A), located in coding exon 2 of the HBB gene, results from a duplication of … (more)
The c.217dupA pathogenic mutation (also known as codons 71/72 insertion A), located in coding exon 2 of the HBB gene, results from a duplication of A at nucleotide position 217, causing a translational frameshift with a predicted alternate stop codon (p.S73Kfs*2). This variant was identified previously in a homozygous individual with beta-thalassemia (Cheng TC et al. Proc. Natl. Acad. Sci. U.S.A., 1984 May;81:2821-5). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 01, 1984)
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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: SCV000036945.4
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Frameshift, +A, codons 71/72, TTAGT to TTTAAGT, was found in Chinese by Cheng et al. (1984).
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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: SCV001244479.1
First in ClinVar: May 04, 2020 Last updated: May 04, 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: SCV002089213.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Molecular Characterization of β-Thalassemia in the Czech and Slovak Populations: Mediterranean, Asian and Unique Mutations. | Divoka M | Hemoglobin | 2016 | PMID: 26956563 |
Molecular basis of transfusion dependent beta-thalassemia major patients in Sabah. | Teh LK | Journal of human genetics | 2014 | PMID: 24369358 |
The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
Simple, efficient, and cost-effective multiplex genotyping with matrix assisted laser desorption/ionization time-of-flight mass spectrometry of hemoglobin beta gene mutations. | Thongnoppakhun W | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19460936 |
Rapid detection of beta-globin gene (HBB) mutations coupling heteroduplex and primer-extension analysis by DHPLC. | Su YN | Human mutation | 2003 | PMID: 12955718 |
beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. | Cheng TC | Proceedings of the National Academy of Sciences of the United States of America | 1984 | PMID: 6585831 |
https://ithanet.eu/db/ithagenes?ithaID=177 | - | - | - | - |
Text-mined citations for rs33969853 ...
HelpRecord last updated May 19, 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.