ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.112del (p.Trp38fs)
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.112del (p.Trp38fs)
Variation ID: 15431 Accession: VCV000015431.111
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226780 (GRCh38) [ NCBI UCSC ] 11: 5248010 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 30, 2017 Apr 20, 2024 Apr 9, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.112del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Trp38fs frameshift NM_000518.5:c.112delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.5226781del NC_000011.9:g.5248011del NG_000007.3:g.70836del NG_042296.1:g.312del NG_046672.1:g.4716del NG_059281.1:g.5292del LRG_1232:g.5292del LRG_1232t1:c.112del LRG_1232p1:p.Trp38fs - Protein change
- W38fs
- Other names
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CD 36/37 (-T)
- Canonical SPDI
- NC_000011.10:5226779:AA: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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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
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 | 1835 | |
| LOC106099062 | - | - | - | GRCh38 | - | 863 |
| LOC107133510 | - | - | - | GRCh38 | - | 1785 |
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
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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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Jan 1, 1991 | RCV000016688.36 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 9, 2023 | RCV000508367.23 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 9, 2018 | RCV000781455.9 | |
| Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004345.9 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 2, 2023 | RCV001078307.18 | |
| Pathogenic (1) |
criteria provided, single submitter
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Apr 13, 2022 | RCV002504797.8 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(-)
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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: SCV001163280.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Sep 20, 2017)
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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: SCV001449909.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 3
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Pathogenic
(Jan 07, 2021)
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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: SCV001156652.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022 |
Comment:
The HBB c.112delT; p.Trp38fs variant (rs63750532), also known as Codons 36/37 (-T) or Frameshift 36/37, is described in the literature in individuals with thalassemia who … (more)
The HBB c.112delT; p.Trp38fs variant (rs63750532), also known as Codons 36/37 (-T) or Frameshift 36/37, is described in the literature in individuals with thalassemia who also carried another pathogenic variant (Rund 1991). This variant is reported as pathogenic in ClinVar (15431). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to c.112delT variant in HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=840&.cgifields=histD Rund D et al. Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):310-4. (less)
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Pathogenic
(Apr 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Heinz body anemia
Hereditary persistence of fetal hemoglobin Dominant beta-thalassemia Hb SS disease alpha Thalassemia Malaria, susceptibility to Beta-thalassemia HBB/LCRB METHEMOGLOBINEMIA, BETA TYPE Erythrocytosis, familial, 6
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002795144.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hemoglobinopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919491.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The HBB c.112delT (p.Trp38GlyfsX24) 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.112delT (p.Trp38GlyfsX24) 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. This variant is absent in 30964 control chromosomes (gnomAD). Multiple publications have cited the variant in individuals affected with BTHAL, observed predominantly in middle eastern countries (Rund_1991, El-Kalla_1997, Huisman_1997). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(May 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:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251903.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810471.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Jul 28, 2021)
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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: SCV000601234.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The HBB c.112del (p.Trp38Glyfs*24) variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant … (more)
The HBB c.112del (p.Trp38Glyfs*24) variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia and has been reported in individuals with beta thalassemia (PMIDs: 32190157 (2020), 2197725 (1990), 1986379 (1991) 28391758 (2017), 31134759 (2019), 26084319 (2015)). Previous names for this variant include Codons 36/37 (-T) and CCT TGG (Pro-Trp). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Apr 09, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001578260.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15431). This variant is also known … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15431). This variant is also known as nonsense 39. This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 1986379, 28391758). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp38Glyfs*24) 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). (less)
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Pathogenic
(Feb 02, 2023)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848885.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Trp38GlyfsX24 (c.112delT or "36/37(-T)") variant in HBB has been reported in over 30 individuals with beta thalassemia (Yılmaz 2019 PMID: 31411089, Yavarian 2001 PMID: … (more)
The p.Trp38GlyfsX24 (c.112delT or "36/37(-T)") variant in HBB has been reported in over 30 individuals with beta thalassemia (Yılmaz 2019 PMID: 31411089, Yavarian 2001 PMID: 11300348, Tekes 2022, Rund 1991 PMID: 1986379, Moradi 2020 PMID: 32869674, Kiani 2007 PMID: 17654071, Jalilian 2017 PMID: 28391758, Guzelgul 2020 PMID: 32664780, Amin 2020 PMID: 33335418). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 15431). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 38 and leads to a premature termination codon 24 amino acids downstream. This is predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting. (less)
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Pathogenic
(Jan 01, 1991)
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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: SCV000036947.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 26, 2018 |
Comment on evidence:
Frameshift, -G, codon 37, TGG to G, was found in a Kurdish patient by Rund et al. (1989, 1991).
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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: SCV001244471.1
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: SCV002089229.1
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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular Characterization and Disease-Related Morbidities of β-Thalassemia Patients from the Northeastern Part of Iraq. | Amin S | International journal of general medicine | 2020 | PMID: 33335418 |
| Distribution of HBB Gene Mutations in the Kurdish Population of Ilam Province, West Iran. | Moradi K | Hemoglobin | 2020 | PMID: 32869674 |
| β-Globin Gene Mutations in Pediatric Patients with β-Thalassemia in the Region of Çukurova, Turkey. | Guzelgul F | Hemoglobin | 2020 | PMID: 32664780 |
| Identification of seven novel variants in the β-globin gene in transfusion-dependent and normal patients. | Aldakeel SA | Archives of medical science : AMS | 2019 | PMID: 32190157 |
| The Spectrum of β-Thalassemia Mutations in Siirt Province, Southeastern Turkey. | Yılmaz S | Hemoglobin | 2019 | PMID: 31411089 |
| Gene expression in blood from an individual with β-thalassemia: An RNA sequence analysis. | Taghavifar F | Molecular genetics & genomic medicine | 2019 | PMID: 31134759 |
| Reliability of the current newborn screening action value for beta thalassaemia disease detection in England: A prospective study. | Daniel Y | Journal of medical screening | 2019 | PMID: 30249157 |
| The Frequency of HBB Mutations Among β-Thalassemia Patients in Hamadan Province, Iran. | Jalilian M | Hemoglobin | 2017 | PMID: 28391758 |
| Interaction of an α-Globin Gene Triplication with β-Globin Gene Mutations in Iranian Patients with β-Thalassemia Intermedia. | Farashi S | Hemoglobin | 2015 | PMID: 26084319 |
| A genetic score for the prediction of beta-thalassemia severity. | Danjou F | Haematologica | 2015 | PMID: 25480500 |
| Frequency of beta-thalassemia or beta-hemoglobinopathy carriers simultaneously affected with alpha-thalassemia in Iran. | Alizadeh S | Clinical laboratory | 2014 | PMID: 25016698 |
| The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
| Comprehensive and efficient HBB mutation analysis for detection of beta-hemoglobinopathies in a pan-ethnic population. | Chan OT | American journal of clinical pathology | 2010 | PMID: 20395516 |
| The molecular analysis of beta-thalassemia mutations in Lorestan Province, Iran. | Kiani AA | Hemoglobin | 2007 | PMID: 17654071 |
| Molecular spectrum of beta-thalassemia in the Iranian Province of Hormozgan. | Yavarian M | Hemoglobin | 2001 | PMID: 11300348 |
| Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. | Huisman TH | Acta haematologica | 1997 | PMID: 9401495 |
| A significant beta-thalassemia heterogeneity in the United Arab Emirates. | el-Kalla S | Hemoglobin | 1997 | PMID: 9140720 |
| Molecular analyses of beta-thalassemia in Iran. | Nozari G | Hemoglobin | 1995 | PMID: 8718703 |
| Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. | Rund D | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 1986379 |
| The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. | Kazazian HH Jr | Seminars in hematology | 1990 | PMID: 2197725 |
| https://ithanet.eu/db/ithagenes?ithaID=134 | - | - | - | - |
| Rund, D., Filon, D., Rachmilewitz, E. A., Cohen, T., Dowling, C., Kazazian, H. H., Oppenheim, A. Molecular analysis of beta-thalassemia in Kurdish Jews: novel mutations and expression studies. (Abstract) Blood 74 (suppl. 1): 220a, 1989. | - | - | - | - |
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Text-mined citations for rs63750532 ...
HelpRecord last updated Nov 25, 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.