Variant summary: The HBB c.230delC (p.Ala77Valfs) 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. The variant of interest was found in controls at an allele frequency of 1/121392, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89 (0.0111803). The variant of interest has been reported in multiple affected individuals via publications, along with reputable databases/clinical laboratories citing the variant as "pathogenic/likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.230del (p.Ala77fs)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.230del (p.Ala77fs)
Variation ID: 15420 Accession: VCV000015420.15
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226662 (GRCh38) [ NCBI UCSC ] 11: 5247892 (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 Mar 29, 2015 Jun 9, 2024 Jan 21, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.230del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Ala77fs frameshift NC_000011.10:g.5226662del NC_000011.9:g.5247892del NG_000007.3:g.70954del NG_042296.1:g.193del NG_046672.1:g.4597del NG_053049.1:g.2983del NG_059281.1:g.5410del LRG_1232:g.5410del LRG_1232t1:c.230del LRG_1232p1:p.Ala77fs - Protein change
- A77fs
- Other names
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CD 76 (-C)
- Canonical SPDI
- NC_000011.10:5226661:G:
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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.
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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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1834 | |
| LOC106099062 | - | - | - | GRCh38 | - | 862 |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Feb 1, 1992 | RCV000016676.29 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2016 | RCV000169256.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV000508493.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697099.1
First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
Comment:
Variant summary: The HBB c.230delC (p.Ala77Valfs) 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.230delC (p.Ala77Valfs) 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. The variant of interest was found in controls at an allele frequency of 1/121392, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89 (0.0111803). The variant of interest has been reported in multiple affected individuals via publications, along with reputable databases/clinical laboratories citing the variant as "pathogenic/likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601260.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
|
|
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Likely pathogenic
(Jul 23, 2014)
|
criteria provided, single submitter
Method: literature only
|
beta Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220545.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001592413.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala77Valfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ala77Valfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3408672, 26076395). ClinVar contains an entry for this variant (Variation ID: 15420). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089211.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Pathogenic
(Feb 01, 1992)
|
no assertion criteria provided
Method: literature only
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BETA-ZERO-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036946.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
Frameshift, -C, codon 76, GCT to GT, was found in an Italian by Di Marzo et al. (1988). Rosatelli et al. (1992) found that this … (more)
Frameshift, -C, codon 76, GCT to GT, was found in an Italian by Di Marzo et al. (1988). Rosatelli et al. (1992) found that this mutation was responsible for 0.7% of the mutations carried by 3,000 beta-thalassemia chromosomes in the Sardinian population. (less)
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Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244483.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Ala77Valfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3408672, 26076395). ClinVar contains an entry for this variant (Variation ID: 15420). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
Variant summary: The HBB c.230delC (p.Ala77Valfs) 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. The variant of interest was found in controls at an allele frequency of 1/121392, which does not exceed the estimated maximal expected allele frequency for a pathogenic HBB variant of 1/89 (0.0111803). The variant of interest has been reported in multiple affected individuals via publications, along with reputable databases/clinical laboratories citing the variant as "pathogenic/likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Ala77Valfs*13) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3408672, 26076395). ClinVar contains an entry for this variant (Variation ID: 15420). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular Basis of β-Thalassemia in the Population of the Aegean Region of Turkey: Identification of A Novel Deletion Mutation. | Ozkinay F | Hemoglobin | 2015 | PMID: 26076395 |
| A genetic score for the prediction of beta-thalassemia severity. | Danjou F | Haematologica | 2015 | PMID: 25480500 |
| The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
| Mosaic segmental uniparental isodisomy and progressive clonal selection: a common mechanism of late onset β-thalassemia major. | Harteveld CL | Haematologica | 2013 | PMID: 22983591 |
| Genetic modifiers of β-thalassemia and clinical severity as assessed by age at first transfusion. | Danjou F | Haematologica | 2012 | PMID: 22271886 |
| 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 |
| The great heterogeneity of thalassemia molecular defects in Sicily. | Giambona A | Human genetics | 1995 | PMID: 7759073 |
| The beta- and delta-thalassemia repository (eighth edition). | Baysal E | Hemoglobin | 1995 | PMID: 7558879 |
| Molecular characterization of beta-thalassemia in the Sardinian population. | Rosatelli MC | American journal of human genetics | 1992 | PMID: 1734721 |
| The spectrum of beta-thalassaemia mutations in Sicily. | Di Marzo R | British journal of haematology | 1988 | PMID: 3408672 |
| Hemoglobin Zürich. A third family presenting with hemolytic reactions to sulfonamides. | Dickerman JD | The American journal of medicine | 1973 | PMID: 4749206 |
| https://ithanet.eu/db/ithagenes?ithaID=181 | - | - | - | - |
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Text-mined citations for rs281864901 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.