Variant summary: The c.323dupG (p.Asn109Glnfs) variant in HBB gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but is present at a low frequency in gnomAD dataset (0.000007; 2/276928 chrs tested), which does not exceed exceed the estimated maximal expected allele frequency of a pathogenic variant (0.011). The variant has been reported in several affected individuals presented with b-thalassemia major via published reports and is cited by reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.323dup (p.Asn109fs)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.323dup (p.Asn109fs)
Variation ID: 439153 Accession: VCV000439153.107
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225718-5225719 (GRCh38) [ NCBI UCSC ] 11: 5246948-5246949 (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 Feb 20, 2024 Oct 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.323dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Asn109fs frameshift NM_000518.4:c.323dup NM_000518.4:c.323dupG NC_000011.10:g.5225721dup NC_000011.9:g.5246951dup NG_000007.3:g.71897dup NG_046672.1:g.3656dup NG_053049.1:g.2042dup NG_059281.1:g.6353dup LRG_1232:g.6353dup LRG_1232t1:c.323dup LRG_1232p1:p.Asn109fs - Protein change
- N109fs
- Other names
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CD 106/107 (+G)
- Canonical SPDI
- NC_000011.10:5225718:CCC:CCCC
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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 | |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
| LOC110006319 | - | - | - | GRCh38 | - | 984 |
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
|
Nov 26, 1987 | RCV000016668.36 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 13, 2023 | RCV000506185.25 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 3, 2017 | RCV000589491.11 |
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
(Jul 03, 2017)
|
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: SCV000697119.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.323dupG (p.Asn109Glnfs) variant in HBB gene is a frameshift change that is predicted to cause loss of normal protein function through protein … (more)
Variant summary: The c.323dupG (p.Asn109Glnfs) variant in HBB gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but is present at a low frequency in gnomAD dataset (0.000007; 2/276928 chrs tested), which does not exceed exceed the estimated maximal expected allele frequency of a pathogenic variant (0.011). The variant has been reported in several affected individuals presented with b-thalassemia major via published reports and is cited by reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601289.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The HBB c.323dup (p.Asn109Glnfs*32) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In … (more)
The HBB c.323dup (p.Asn109Glnfs*32) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, the variant has been reported in individuals with beta-thalassemia (PMID: 3683554 (1987), 23590658 (2013)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001384504.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the HBB protein. This variant is present in population databases (rs606231216, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3683554). ClinVar contains an entry for this variant (Variation ID: 439153). This variant disrupts a region of the HBB protein in which other variant(s) (p.Val127Glufs*8) have been determined to be pathogenic (PMID: 8535446, 31190580). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048071.4
First in ClinVar: Jan 08, 2022 Last updated: Feb 20, 2024 |
Comment:
The HBB c.323dupG; p.Asn109GlnfsTer32 variant (rs35225141, HbVar ID: 945), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta(0) thalassemia … (more)
The HBB c.323dupG; p.Asn109GlnfsTer32 variant (rs35225141, HbVar ID: 945), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta(0) thalassemia (Hoppe 2013), and found with another pathogenic HBB variant (Wong 1987). This variant is reported as pathogenic in ClinVar (Variation ID: 439153). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating 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 HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554. (less)
|
|
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Pathogenic
(Nov 26, 1987)
|
no assertion criteria provided
Method: literature only
|
BETA-ZERO-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036938.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Frameshift, +G, codons 106/107, CTGGGC to CTGGGGG, was found in American blacks by Wong et al. (1987).
|
|
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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: SCV001244495.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
Comment:
Comment:
The HBB c.323dup (p.Asn109Glnfs*32) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, the variant has been reported in individuals with beta-thalassemia (PMID: 3683554 (1987), 23590658 (2013)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the HBB protein. This variant is present in population databases (rs606231216, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3683554). ClinVar contains an entry for this variant (Variation ID: 439153). This variant disrupts a region of the HBB protein in which other variant(s) (p.Val127Glufs*8) have been determined to be pathogenic (PMID: 8535446, 31190580). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The HBB c.323dupG; p.Asn109GlnfsTer32 variant (rs35225141, HbVar ID: 945), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta(0) thalassemia (Hoppe 2013), and found with another pathogenic HBB variant (Wong 1987). This variant is reported as pathogenic in ClinVar (Variation ID: 439153). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating 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 HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554.
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 c.323dupG (p.Asn109Glnfs) variant in HBB gene is a frameshift change that is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but is present at a low frequency in gnomAD dataset (0.000007; 2/276928 chrs tested), which does not exceed exceed the estimated maximal expected allele frequency of a pathogenic variant (0.011). The variant has been reported in several affected individuals presented with b-thalassemia major via published reports and is cited by reputable databases/clinical laboratories as Pathogenic. Taking together, the variant was classified as Pathogenic.
Comment:
The HBB c.323dup (p.Asn109Glnfs*32) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, the variant has been reported in individuals with beta-thalassemia (PMID: 3683554 (1987), 23590658 (2013)). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Asn109Glnfs*32) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the HBB protein. This variant is present in population databases (rs606231216, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with HBB-related conditions (PMID: 3683554). ClinVar contains an entry for this variant (Variation ID: 439153). This variant disrupts a region of the HBB protein in which other variant(s) (p.Val127Glufs*8) have been determined to be pathogenic (PMID: 8535446, 31190580). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The HBB c.323dupG; p.Asn109GlnfsTer32 variant (rs35225141, HbVar ID: 945), also known as c.321_322insG and Codon 106/107 (+G), has been reported in individuals with beta(0) thalassemia (Hoppe 2013), and found with another pathogenic HBB variant (Wong 1987). This variant is reported as pathogenic in ClinVar (Variation ID: 439153). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by duplicating 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 HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Compound Heterozygote of Hb S (HBB: c.20A>T)/Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG): Report of Four Cases from Odisha State, India. | Dehury S | Hemoglobin | 2019 | PMID: 31190580 |
| Prenatal and newborn screening for hemoglobinopathies. | Hoppe CC | International journal of laboratory hematology | 2013 | PMID: 23590658 |
| 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 |
| Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. | Sinha S | The HUGO journal | 2009 | PMID: 21119755 |
| Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population. | Colah R | Blood cells, molecules & diseases | 2009 | PMID: 19254853 |
| Analysis of beta globin mutations in the Indian population: presence of rare and novel mutations and region-wise heterogeneity. | Edison ES | Clinical genetics | 2008 | PMID: 18294253 |
| Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis. | Shaji RV | Clinical chemistry | 2003 | PMID: 12709369 |
| 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 |
| Liver iron depletion and toxicity of the iron chelator deferiprone (L1, CP20) in the guinea pig. | Wong A | Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine | 1997 | PMID: 9353871 |
| Novel seventeen basepair deletion in exon 3 of the beta-globin gene. | Waye JS | Human mutation | 1995 | PMID: 8535446 |
| Reverse dot-blot detection of the African-American beta-thalassemia mutations. | Sutcharitchan P | Blood | 1995 | PMID: 7632967 |
| Molecular characterization of beta-thalassemia in Egyptians. | Hussein IR | Human mutation | 1993 | PMID: 8477263 |
| Mean corpuscular volume of heterozygotes for beta-thalassemia correlates with the severity of mutations. | Rund D | Blood | 1992 | PMID: 1728311 |
| Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. | Kazazian HH Jr | Blood | 1992 | PMID: 1586746 |
| Molecular characterization of Hb S(C) beta-thalassemia in American blacks. | Gonzalez-Redondo JM | American journal of hematology | 1991 | PMID: 1897518 |
| Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. | Gonzalez-Redondo JM | Blood | 1988 | PMID: 2458145 |
| Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. | Wong C | Nature | 1987 | PMID: 3683554 |
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Text-mined citations for rs35225141 ...
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 Nov 03, 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.