ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.25_26del (p.Lys9fs)
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.25_26del (p.Lys9fs)
Variation ID: 15413 Accession: VCV000015413.114
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 11p15.4 11: 5226996-5226997 (GRCh38) [ NCBI UCSC ] 11: 5248226-5248227 (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 Apr 4, 2013 Apr 15, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.25_26del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Lys9fs frameshift NC_000011.10:g.5226996_5226997del NC_000011.9:g.5248226_5248227del NG_000007.3:g.70619_70620del NG_042296.1:g.527_528del NG_046672.1:g.4931_4932del NG_059281.1:g.5075_5076del LRG_1232:g.5075_5076del LRG_1232t1:c.25_26del LRG_1232p1:p.Lys9fs - Protein change
- K9fs
- Other names
- cd8-AA
- CD 8 (-AA)
- Canonical SPDI
- NC_000011.10:5226995: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 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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Pathogenic (1) |
no assertion criteria provided
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Apr 1, 1995 | RCV000016669.34 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2019 | RCV000029972.20 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 15, 2024 | RCV000506563.37 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004358.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV002288500.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2024 | RCV003989287.1 |
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
(-)
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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: SCV001163294.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446696.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Amyotrophic lateral sclerosis (present) , Spasticity (present) , Dysarthria (present) , Fasciculations (present) , Muscular atrophy (present)
Sex: male
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Pathogenic
(Mar 08, 2016)
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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: SCV001450319.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 17
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Pathogenic
(Nov 12, 2016)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601261.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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Pathogenic
(Apr 27, 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: SCV002581330.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV003841708.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015413 / PMID: 3828533). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Reduced beta/alpha synthesis ratio (present) , Short stature (present) , Growth delay (present) , Failure to thrive (present) , Decreased body weight (present) , Bone … (more)
Reduced beta/alpha synthesis ratio (present) , Short stature (present) , Growth delay (present) , Failure to thrive (present) , Decreased body weight (present) , Bone pain (present) (less)
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Pathogenic
(Jan 15, 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: SCV000953169.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys9Valfs*14) 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.Lys9Valfs*14) 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 (rs35497102, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with HBB-related conditions (PMID: 3828533, 25405919, 26771086, 28391758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15413). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 25, 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: SCV001160183.6
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The HBB c.25_26del; p.Lys9ValfsTer14 variant (also known as Lys8fsTer14 when numbered from the mature protein or as Codon 8 (-AA), rs35497102, Hbvar ID: 785) has … (more)
The HBB c.25_26del; p.Lys9ValfsTer14 variant (also known as Lys8fsTer14 when numbered from the mature protein or as Codon 8 (-AA), rs35497102, Hbvar ID: 785) has been reported in multiple patients with beta (0) thalassemia, both in the homozygous state and in trans to another pathogenic variant (Jalilian 2017, Orkin 1981, HbVar database and references therein). 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 deleting two nucleotides, 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: https://globin.bx.psu.edu/hbvar/hbvar.html Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Orkin S et al. Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. J Biol Chem. 1981; 256(19):9782-4. PMID: 6985481. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Malaria, susceptibility to
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807714.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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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: SCV001194042.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000518.4(HBB):c.25_26delAA(aka K9Vfs*14) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a … (more)
NM_000518.4(HBB):c.25_26delAA(aka K9Vfs*14) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 22851993, 25155404, 23321370, 2200760, 6985481 and 22110956. Classification of NM_000518.4(HBB):c.25_26delAA(aka K9Vfs*14) 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
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Beta Thalassemia
(autosomal recessive)
Affected status: unknown, yes
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052627.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 20
Observation 2:
Tissue: Blood
Observation 3:
Tissue: Blood
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Pathogenic
(Dec 17, 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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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818122.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Pathogenic
(Dec 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961264.14
First in ClinVar: Oct 08, 2021 Last updated: Apr 15, 2024 |
Comment:
HBB: PVS1, PS4:Moderate
Number of individuals with the variant: 4
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Pathogenic
(Apr 01, 1995)
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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: SCV000036939.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 07, 2021 |
Comment on evidence:
A frameshift mutation, -AA in codon 8, AAG to G, in the HBB gene was found in a Turkish patient with beta-zero-thalassemia (613985) by Orkin … (more)
A frameshift mutation, -AA in codon 8, AAG to G, in the HBB gene was found in a Turkish patient with beta-zero-thalassemia (613985) by Orkin and Goff (1981). This mutation was also found in homozygous state in DNA from the archaeologic remains of a child with severe bone pathology consistent with thalassemia (Filon et al., 1995). The remains came from a grave thought to date to the Ottoman period, sometime between the 16th and 19th centuries. From the tooth development, it was estimated that the child died at the age of about 8 years, whereas patients with this mutation would be expected to be transfusion-dependent from early infancy. Filon et al. (1995) also found a rare DNA polymorphism: a C-to-T transition in the second codon of the HBB gene that did not alter the corresponding amino acid. This polymorphism is found in 13% of present-day Mediterranean beta-thalassemia chromosomes and is part of a haplotype (haplotype IV) that is associated with relatively high levels of fetal hemoglobin. The disease may have run a milder course because of linkage to haplotype IV. (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: SCV001244554.1
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: SCV002091612.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Oct 09, 2023)
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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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Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041636.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
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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: SCV000040706.4
First in ClinVar: Apr 04, 2013 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 Frequency of HBB Mutations Among β-Thalassemia Patients in Hamadan Province, Iran. | Jalilian M | Hemoglobin | 2017 | PMID: 28391758 |
The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β(0) -thalassaemia homozygotes. | Jiang Z | British journal of haematology | 2016 | PMID: 26771086 |
Non-thalassemic phenotype associated with the -83 (G > A) mutation of the β-globin gene promoter (HBB: c.-133G > A). | Waye JS | Hemoglobin | 2014 | PMID: 25405919 |
The spectrum of β-thalassemia mutations in Hatay, Turkey: reporting three new mutations. | Aldemir O | Hemoglobin | 2014 | PMID: 25155404 |
The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
The spectrum of β-thalassemia mutations in Gaza Strip, Palestine. | Sirdah MM | Blood cells, molecules & diseases | 2013 | PMID: 23321370 |
β-Thalassemia mutations and hemoglobinopathies in Adana, Turkey: results from a single center study. | Guvenc B | Archives of medical science : AMS | 2012 | PMID: 22851993 |
β-Thalassemia Mutations among Transfusion-Dependent Thalassemia Major Patients in Northern Iraq. | Al-Allawi NA | Molecular biology international | 2010 | PMID: 22110956 |
ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia. | Shammas C | Clinical chemistry and laboratory medicine | 2010 | PMID: 20704537 |
Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE). | Al-Gazali L | Human mutation | 2010 | PMID: 20437613 |
Strategies and clinical outcome of 250 cycles of Preimplantation Genetic Diagnosis for single gene disorders. | Fiorentino F | Human reproduction (Oxford, England) | 2006 | PMID: 16311287 |
Real-time PCR for single-cell genotyping in sickle cell and thalassemia syndromes as a rapid, accurate, reliable, and widely applicable protocol for preimplantation genetic diagnosis. | Vrettou C | Human mutation | 2004 | PMID: 15108284 |
Reliability of DHPLC in mutational screening of beta-globin (HBB) alleles. | Colosimo A | Human mutation | 2002 | PMID: 11857746 |
A significant beta-thalassemia heterogeneity in the United Arab Emirates. | el-Kalla S | Hemoglobin | 1997 | PMID: 9140720 |
Sequence analysis reveals a beta-thalassaemia mutation in the DNA of skeletal remains from the archaeological site of Akhziv, Israel. | Filon D | Nature genetics | 1995 | PMID: 7795641 |
The beta-thalassaemia mutations in the population of Cyprus. | Baysal E | British journal of haematology | 1992 | PMID: 1390250 |
Beta-thalassemia, HB S-beta-thalassemia and sickle cell anemia among Tunisians. | Fattoum S | Hemoglobin | 1991 | PMID: 1917531 |
Beta-thalassemia in Turkey. | Oner R | Hemoglobin | 1990 | PMID: 2200760 |
Mild and severe beta-thalassemia among homozygotes from Turkey: identification of the types by hybridization of amplified DNA with synthetic probes. | Diaz-Chico JC | Blood | 1988 | PMID: 2446680 |
The molecular basis of beta-thalassemia in Lebanon: application to prenatal diagnosis. | Chehab FF | Blood | 1987 | PMID: 3828533 |
Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. | Wong C | Nature | 1987 | PMID: 3683554 |
Beta zero-thalassemia in association with a gamma-globin gene quadruplication. | Yang KG | Blood | 1986 | PMID: 2430648 |
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 |
mRNA-deficient beta o-thalassemia results from a single nucleotide deletion. | Kinniburgh AJ | Nucleic acids research | 1982 | PMID: 6292840 |
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 |
Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. | Orkin SH | The Journal of biological chemistry | 1981 | PMID: 6985481 |
Heterogeneity of DNA deletion in gamma delta beta-thalassemia. | Orkin SH | The Journal of clinical investigation | 1981 | PMID: 6162860 |
https://ithanet.eu/db/ithagenes?ithaID=61 | - | - | - | - |
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Text-mined citations for rs35497102 ...
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.