ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.118C>T (p.Gln40Ter)
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.118C>T (p.Gln40Ter)
Variation ID: 15402 Accession: VCV000015402.135
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226774 (GRCh38) [ NCBI UCSC ] 11: 5248004 (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 Oct 9, 2016 Oct 8, 2024 Mar 20, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000518.5:c.118C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Gln40Ter nonsense NC_000011.10:g.5226774G>A NC_000011.9:g.5248004G>A NG_000007.3:g.70842C>T NG_042296.1:g.305G>A NG_046672.1:g.4709G>A NG_059281.1:g.5298C>T LRG_1232:g.5298C>T LRG_1232t1:c.118C>T LRG_1232p1:p.Gln40Ter - Protein change
- Q40*
- Other names
- Q39*
- cd39C>T
- CD 39 (CAG>TAG)
- Canonical SPDI
- NC_000011.10:5226773:G:A
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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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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00023
The Genome Aggregation Database (gnomAD) 0.00026
The Genome Aggregation Database (gnomAD), exomes 0.00033
Exome Aggregation Consortium (ExAC) 0.00042
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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. |
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HBB | - | - |
GRCh38 GRCh37 |
22 | 1832 | |
LOC106099062 | - | - | - | GRCh38 | - | 860 |
LOC107133510 | - | - | - | GRCh38 | - | 1782 |
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
|
Feb 1, 1992 | RCV000016656.33 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000254827.49 | |
Pathogenic (14) |
criteria provided, multiple submitters, no conflicts
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Mar 20, 2024 | RCV000379715.36 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 9, 2023 | RCV001004570.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 28, 2019 | RCV001197268.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2022 | RCV002221479.11 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV002288499.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV002476976.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2016 | RCV002336086.9 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 24, 2023 | RCV004532366.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 17, 2024 | RCV003987324.3 | |
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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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hb SS disease
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163654.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810470.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
Pathogenic
(Mar 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934477.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
|
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Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579890.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM3, PM2_SUP, PP4
|
Number of individuals with the variant: 2
Sex: male
|
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Pathogenic
(Feb 01, 2022)
|
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 TYPE Erythrocytosis, familial, 6
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893887.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 17, 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
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003921007.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
_x000D_ Criteria applied: PVS1, PS3, PS4, PP4
|
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Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000950883.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln40*) 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.Gln40*) 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 (rs11549407, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta-thalassemia (PMID: 8095930, 25572186, 27427187, 28366028). This variant is also known as p.Gln39X. ClinVar contains an entry for this variant (Variation ID: 15402). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603892.9
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The Codon 39 C>T variant (HBB c.118C>T; p.Gln40Ter, also known as Gln39Ter when numbered from the mature protein, rs11549407, HbVar ID: 845) induces an early … (more)
The Codon 39 C>T variant (HBB c.118C>T; p.Gln40Ter, also known as Gln39Ter when numbered from the mature protein, rs11549407, HbVar ID: 845) induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant is one of the most common Mediterranean beta(0) thalassemia variants (see HbVar link and references therein) and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html (less)
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Pathogenic
(Feb 11, 2016)
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criteria provided, single submitter
Method: research
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown,
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000584091.1 First in ClinVar: Jul 29, 2017 Last updated: Jul 29, 2017 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
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Pathogenic
(Mar 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595094.1
First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017 |
|
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Pathogenic
(Apr 08, 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: SCV000697073.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The c.118C>T variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known … (more)
Variant summary: The c.118C>T variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known diease mechanism in hemoglobinopathy. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.217dupA, c.230delC, c.251delG, etc. ). This variant is found in 51/121354 control chromosomes at a frequency of 0.0004203, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant is a well-known common pathogenic variant in Sardinian and other populations (Danjou_2012, Sirdah_2013). Multiple reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic. (less)
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Pathogenic
(Apr 21, 2016)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331533.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
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Pathogenic
(Oct 19, 2017)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449993.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 15
|
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Pathogenic
(Mar 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
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alpha Thalassemia
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367905.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1.
|
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Pathogenic
(Dec 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047291.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
Comment:
The HBB c.118C>T (p.Gln40*) variant causes the premature termination of beta-globin protein synthesis and is associated with beta-zero thalassemia (see HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), and PMID: 6457059 … (more)
The HBB c.118C>T (p.Gln40*) variant causes the premature termination of beta-globin protein synthesis and is associated with beta-zero thalassemia (see HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), and PMID: 6457059 (1981), 6985481 (1981), 6896219 (1982)). Previous names for this pathogenic variant include codon 39 (C>T) and Gln39X. (less)
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Pathogenic
(Feb 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499063.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PVS1, PS3, PM3
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Pathogenic
(Apr 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Heinz body anemia
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002499425.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The c.118C>T;p.(Gln40*) variant creates a premature translational stop signal in the HBB gene. It is expected to result in an absent or disrupted protein product … (more)
The c.118C>T;p.(Gln40*) variant creates a premature translational stop signal in the HBB gene. It is expected to result in an absent or disrupted protein product -PVS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 2867271)PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 15402; PMID: 20301599; 27199182; 28361595; 27829304; 28670940; 28366028; 26897028; 32039214; 26366554; 6457059; 28366028) - PS4. The variant is present at low allele frequencies population databases (rs11549407 – gnomAD 0.002695%; ABraOM 0.000854 frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Gln40*) was detected in trans with a pathogenic variant (PMID: 28361595; 26956563) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
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Pathogenic
(Mar 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321762.10
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
One of the major beta-thalassemia alleles in the Mediterranean area (HbVar ID 845; Giardine et al., 2014); Nonsense variant predicted to result in protein truncation … (more)
One of the major beta-thalassemia alleles in the Mediterranean area (HbVar ID 845; Giardine et al., 2014); Nonsense 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; Published functional studies demonstrate a damaging effect with significantly reduced mRNA expression level in R40X transfected Hela cells with no protein detected, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay (Neu-Yilik et al., 2011); Identified in multiple individuals with beta-thalassemia minor or beta-thalassemia trait referred for genetic testing at GeneDx; Q40X has also been reported as Q39X using alternative nomenclature; This variant is associated with the following publications: (PMID: 2867271, 21417574, 25087612, 22975760, 1734721, 25572186, 21228398, 20301599, 6457059, 27821015, 8095930, 28670940, 27959697, 28366028, 24137000, 30665703, 31784700, 27427187, 32248411, 8103502, 34426522, 8195005, 1795494, 33326653, 31589614, 15609277, 9629495, 33339817, 9163586, 2577233, 21389146) (less)
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Pathogenic
(Jan 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003806990.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS4 strong
Number of individuals with the variant: 1
Clinical Features:
Macrocephaly (present) , Melanocytic nevus (present) , Short neck (present) , Short stature (present) , Hypertelorism (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
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Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841607.1
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: 0.031%). 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: 0.031%). 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: VCV000015402 / PMID: 6457059). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Chronic hemolytic anemia (present) , Arthralgia (present) , Hypochromic microcytic anemia (present)
|
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Pathogenic
(May 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hb SS disease
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004014695.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The HBB c.118C>T (p.Gln40Ter) nonsense variant, also referred to as p.Gln39Ter, results in the loss of normal protein function through nonsense-mediated mRNA decay. This variant … (more)
The HBB c.118C>T (p.Gln40Ter) nonsense variant, also referred to as p.Gln39Ter, results in the loss of normal protein function through nonsense-mediated mRNA decay. This variant is one of the commonly identified pathogenic variants in individuals with beta-thalassemia from the Mediterranean region, accounting for most cases in Sardinia (PMID: 23637309). The p.Gln40Ter variant has been reported in a homozygous or compound heterozygous state in more than 300 individuals with different forms of beta-thalassemia (PMID: 9163586; 22271886; 23321370; 27199182; 33000750). The frequency of this allele in the Genome Aggregation Database is 0.000655 in the Latino/Admixed American population (version 3.1.2). A functional study using HeLa cells showed reduced mRNA expression with no protein detected in cells transfected with the variant compared to wildtype, suggesting the variant undergoes nonsense mediated mRNA decay (PMID: 21389146). Based on the available evidence, the c.118C>T (p.Gln40Ter) variant is classified as pathogenic for sickle cell disease. (less)
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Pathogenic
(Feb 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024956.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Malaria, susceptibility to
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804799.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
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Pathogenic
(Mar 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
beta Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365782.2
First in ClinVar: Jul 04, 2020 Last updated: Apr 20, 2024 |
Comment:
The p.Gln40X variant, also reported as p.Gln39X, in HBB is a well-known pathogenic variant that has been identified in the homozygous or compound heterozygous state … (more)
The p.Gln40X variant, also reported as p.Gln39X, in HBB is a well-known pathogenic variant that has been identified in the homozygous or compound heterozygous state with another pathogenic variant in >300 individuals with beta thalassemia (Rosatelli 1992 PMID: 1734721, Ghedira 2011 PMID: 21417574, Danjou 2012 PMID: 22271886, Sirdah 2013 PMID: 23321370, Herrera 2015 PMID: 25572186, Gallagher 2016 PMID: 27821015, Hussain 2017 PMID: 28670940, Carrocini 2017 PMID: 28366028). It has also been reported by other clinical laboratories in ClinVar (Variation ID 15402). Additionally, it has been identified in 0.02% (14/60012) of Admixed American and 0.02% (80/12912216/11800180) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 40 and has shown decreased mRNA expression level with no protein detected in p.Arg40X transfected Hela cells, suggesting that the variant undergoes nonsense-mediated mRNA decay (Neu-Yilik 2011 PMID: 21389146). Biallelic 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, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002643506.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q40* pathogenic mutation (also known as c.118C>T and p.Q39X), located in coding exon 2 of the HBB gene, results from a C to T … (more)
The p.Q40* pathogenic mutation (also known as c.118C>T and p.Q39X), located in coding exon 2 of the HBB gene, results from a C to T substitution at nucleotide position 118. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation was first reported in the Sardinian population and in an Italian individual with beta0-thalassemia (Trecartin RF et al. J. Clin. Invest., 1981 Oct;68:1012-7; Orkin SH et al. J. Biol. Chem., 1981 Oct;256:9782-4). In addition to the clinical data presented in the literature, 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, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062957.17
First in ClinVar: Jan 22, 2022 Last updated: Oct 08, 2024 |
Comment:
HBB: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 5
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Pathogenic
(Dec 10, 2019)
|
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: SCV001194055.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_000518.4(HBB):c.118C>T(Q40*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that Q40* is associated with beta thalassemia and is classified … (more)
NM_000518.4(HBB):c.118C>T(Q40*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that Q40* is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 1734721 and 21417574. Classification of NM_000518.4(HBB):c.118C>T(Q40*) 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
(Apr 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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BETA-THALASSEMIA
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001445880.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This nonsense variant found in exon 2 of 3 is predicted to result in loss of normal protein function. This variant has been previously reported … (more)
This nonsense variant found in exon 2 of 3 is predicted to result in loss of normal protein function. This variant has been previously reported in trans with a second HBB variant in individuals affected with with beta-thalassemia (PMID: 6457059, 23637309, 21417574, 27821015, 20301599). The variant was been classified as Pathogenic by multiple clinical laboratories in the ClinVar database (Variation ID: 15402). Functional studies of the variant using transfected Hela cells demonstrate significantly reduced mRNA expression with no protein detected, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay (PMID: 21389146). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (87/282760). Based on the available evidence the c.118C>T (p.Gln40Ter) variant is classified as Pathogenic. (less)
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Pathogenic
(Feb 03, 2020)
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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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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761425.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Beta-thalassemia HBB/LCRB
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051809.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 10, 2016)
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no assertion criteria provided
Method: clinical testing
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Beta-thalassemia HBB/LCRB
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000328728.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.118C>T) and KANSL1 (NM_001193466.1, c.985_995del) in one individual with reported features of delayed motor milestones, delayed … (more)
Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.118C>T) and KANSL1 (NM_001193466.1, c.985_995del) in one individual with reported features of delayed motor milestones, delayed speech, intellectual disability, dysmorphic features, familial short stature, minor beta-thalassemia, eye anomalies (strabismus, nearsighted) and cafe au lait spot on right upper chest. Brain MRI showed asymmetric prominent ventricles, possible undermyelination and amygdalo/hippocampal dysgenesis. The same variant has been found in 4 additional individuals with beta thalassemia trait. (less)
Number of individuals with the variant: 5
Family history: yes
Age: 2-12 years
Sex: mixed
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Pathogenic
(Feb 01, 1992)
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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: SCV000036925.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Chehab et al. (1986) found evidence for new mutation in the codon at beta-39 from CAG (glutamine) to the stop codon TAG. The beta-39 nonsense … (more)
Chehab et al. (1986) found evidence for new mutation in the codon at beta-39 from CAG (glutamine) to the stop codon TAG. The beta-39 nonsense mutation is the second most common beta-thalassemia (613985) lesion in Italy, accounting for a third of cases, and the most common in Sardinia, accounting for 90% of cases there. In Sardinia, the beta-39 mutation has been identified with 9 different haplotypes. All this suggested to Chehab et al. (1986) that beta-39 is a mutation hotspot. Trecartin et al. (1981) found that the form of beta-zero-thalassemia that is predominant in Sardinia is caused by a single nucleotide mutation at the position corresponding to amino acid number 39 and converting a glutamine codon (CAG) to an amber termination codon (UAG). (Epstein et al. (1963) described 'amber' mutants of phage T4 in a frequently cited paper in a Cold Spring Harbor Symposium on Quantitative Biology. The origin of the unusual name 'amber' is, as Witkowski (1990) called it, 'an interesting footnote in the history of molecular biology.' Edgar (1966) recounted that R. H. Epstein and C. M. Steinberg, then at the California Institute of Technology, had promised Harris Bernstein, then at Yale University, that the mutants, if any were found, would be named after his mother. They were found and were named 'amber,' the English equivalent of 'Bernstein.' The other 2 'stop' codons, UGA and UAA, are sometimes referred to as 'opal' and 'ochre,' respectively.) Rosatelli et al. (1992) used denaturing gradient gel electrophoresis (DGGE) followed by direct sequence analysis of amplified DNA to study 3,000 beta-thalassemia chromosomes in the Sardinian population. They confirmed that the predominant mutation, present in 95.7% of beta-thalassemia chromosomes, was gln39-to-ter. (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: SCV001244540.1
First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020 |
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Pathogenic
(Nov 24, 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: SCV004171648.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(Aug 25, 2019)
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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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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132982.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Sep 16, 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: SCV001453782.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Dec 24, 2023)
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no assertion criteria provided
Method: clinical testing
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HBB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004721372.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The HBB c.118C>T variant is predicted to result in premature protein termination (p.Gln40*). The c.118C>T change is a pathogenic founder variant in Sardina and is … (more)
The HBB c.118C>T variant is predicted to result in premature protein termination (p.Gln40*). The c.118C>T change is a pathogenic founder variant in Sardina and is also referred to as codon 39C>T (Rosatelli MC et al 1992. PubMed ID: 1734721; Trecartin et al 1981. PubMed ID: 6457059; Sirdah et al. 2013. PubMed ID: 23321370). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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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: SCV000040703.4
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 |
---|---|---|---|---|
Beta-Thalassemia. | Adam MP | - | 2024 | PMID: 20301599 |
Genotypic groups as risk factors for cardiac magnetic resonance abnormalities and complications in thalassemia major: a large, multicentre study. | Pistoia L | Blood transfusion = Trasfusione del sangue | 2021 | PMID: 33000750 |
Rare Co-occurrence of Beta-Thalassemia and Pseudoxanthoma elasticum: Novel Biomolecular Findings. | Boraldi F | Frontiers in medicine | 2020 | PMID: 32039214 |
Rare β-Globin Gene Mutations in Pakistan. | Hussain A | Hemoglobin | 2017 | PMID: 28670940 |
Mutational Profile of Homozygous β-Thalassemia in Rio de Janeiro, Brazil. | Carrocini GCS | Hemoglobin | 2017 | PMID: 28366028 |
The Molecular Spectrum of β- and α-Thalassemia Mutations in Non-Endemic Umbria, Central Italy. | Gorello P | Hemoglobin | 2016 | PMID: 28361595 |
First description of the rs45496295 polymorphism of the C/EBPE gene in β-thalassemia intermedia patients. | Mejri A | Hemoglobin | 2016 | PMID: 27829304 |
Mutation in a Highly Conserved COOH-Terminal Residue of Krüppel-Like Factor 1 Associated with Elevated Hb F in a Compound Heterozygous β-Thalassemia Patient with a Nontransfusion-Dependent Thalassemia Phenotype. | Gallagher PG | Hemoglobin | 2016 | PMID: 27821015 |
Detection of new pathogenic mutations in patients with congenital haemolytic anaemia using next-generation sequencing. | Del Orbe Barreto R | International journal of laboratory hematology | 2016 | PMID: 27427187 |
The molecular spectrum and distribution of haemoglobinopathies in Cyprus: a 20-year retrospective study. | Kountouris P | Scientific reports | 2016 | PMID: 27199182 |
Molecular Characterization of β-Thalassemia in the Czech and Slovak Populations: Mediterranean, Asian and Unique Mutations. | Divoka M | Hemoglobin | 2016 | PMID: 26956563 |
Structural and Functional Insights on an Uncharacterized Aγ-Globin-Gene Polymorphism Present in Four β0-Thalassemia Families with High Fetal Hemoglobin Levels. | Bianchi N | Molecular diagnosis & therapy | 2016 | PMID: 26897028 |
Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. | Sidore C | Nature genetics | 2015 | PMID: 26366554 |
Identification of a novel mutation in the β-globin gene 3' untranslated region (HBB: c.*+118A > G) in Spain. | Herrera MA | Hemoglobin | 2015 | PMID: 25572186 |
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
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 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion. | Danjou F | Haematologica | 2012 | PMID: 22271886 |
A second observation of the rare frameshift mutation in the β-globin gene: codon 46 (+A) (Hbb:c.138_139insA). | Ghedira ES | Hemoglobin | 2011 | PMID: 21417574 |
Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. | Neu-Yilik G | RNA (New York, N.Y.) | 2011 | PMID: 21389146 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Beta-thalassaemia in the immigrant and non-immigrant German populations. | Vetter B | British journal of haematology | 1997 | PMID: 9163586 |
DNA polymorphisms associated with Hb D-Los Angeles [beta 121(GH4)Glu-->Gln] in southern Italy. | Fioretti G | Hemoglobin | 1993 | PMID: 8095930 |
Molecular characterization of beta-thalassemia in the Sardinian population. | Rosatelli MC | American journal of human genetics | 1992 | PMID: 1734721 |
Spontaneous mutation in beta-thalassaemia producing the same nucleotide substitution as that in a common hereditary form. | Chehab FF | Lancet (London, England) | 1986 | PMID: 2867271 |
A new nonsense mutation as the molecular basis for beta thalassaemia. | Gorski J | Journal of molecular biology | 1982 | PMID: 6896219 |
Nonsense and frameshift mutations in beta 0-thalassemia detected in cloned beta-globin genes. | Orkin SH | The Journal of biological chemistry | 1981 | PMID: 6985481 |
beta zero thalassemia in Sardinia is caused by a nonsense mutation. | Trecartin RF | The Journal of clinical investigation | 1981 | PMID: 6457059 |
Heterogeneity of DNA deletion in gamma delta beta-thalassemia. | Orkin SH | The Journal of clinical investigation | 1981 | PMID: 6162860 |
Edgar, R. S. Conditional lethals. In: Cairns, J., Stent, G. S., Watson, J. D. Phage and the Origins of Molecular Biology. Cold Spring Harbor, New York: Cold Spring Harbor Laboratory (pub.) 166-170, 1966. | - | - | - | - |
Epstein, R. H., Bolle, A., Steinberg, C. M., Kellenberger, E., Boy de la Tour, E., Chevalley, R., Edgar, R. S., Susman, M., Denhardt, G. H., Lielausis, A. Physiological studies of conditional lethal mutants of bacteriophage T4D. Cold Spring Harbor Symp. Quant. Biol. 28: 375-394, 1963. | - | - | - | - |
http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=845 | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HBB | - | - | - | - |
https://ithanet.eu/db/ithagenes?ithaID=142 | - | - | - | - |
Witkowski, J. A. The 51 most-cited articles in the Cold Spring Harbor Symposia on Quantitative Biology. Curr. Contents 33(28): 7-16, 1990. | - | - | - | - |
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Text-mined citations for rs11549407 ...
HelpRecord last updated Oct 08, 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.