ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.92+1G>T
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.
(16)
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
16
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.92+1G>T
Variation ID: 15437 Accession: VCV000015437.116
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226929 (GRCh38) [ NCBI UCSC ] 11: 5248159 (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 Oct 8, 2024 Jan 28, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.92+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000011.10:g.5226929C>A NC_000011.9:g.5248159C>A NG_000007.3:g.70687G>T NG_042296.1:g.460C>A NG_046672.1:g.4864C>A NG_059281.1:g.5143G>T LRG_1232:g.5143G>T LRG_1232t1:c.92+1G>T - Protein change
- -
- Other names
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IVS I-1 (G>T)
IVS1, G-T, +1
- Canonical SPDI
- NC_000011.10:5226928:C: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 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 27, 2017 | RCV000016695.36 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 5, 2022 | RCV000169505.16 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000507580.36 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 20, 2021 | RCV001004349.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 9, 2017 | RCV002444432.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 13, 2022 | RCV002482875.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 7, 2024 | RCV004689419.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 22, 2023 | RCV004532369.2 |
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 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601325.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
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Pathogenic
(Apr 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697154.2
First in ClinVar: Mar 29, 2015 Last updated: May 16, 2022 |
Comment:
Variant summary: HBB c.92+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: HBB c.92+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 7.2e-05 in 251366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (7.2e-05 vs 0.011), allowing no conclusion about variant significance. c.92+1G>T has been reported in the literature in numerous individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Likely pathogenic
(Dec 18, 2014)
|
criteria provided, single submitter
Method: literature only
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beta Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220968.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Apr 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
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: SCV002803430.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001759119.3
First in ClinVar: Jul 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene … (more)
Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8199027, 16044458, 10975438, 2064964, 26865073, 26715484, 26554253, 22975760, 25525159, 10870879, 9225979, 18294253, 26291967, 12885342, 19090545, 18759082, 19000664, 19843386, 19254853, 28635337, 6714226, 27263053, 30275481, 9629495, 31890591, 9163586, 8012089) (less)
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Pathogenic
(Jan 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163284.2
First in ClinVar: Feb 29, 2020 Last updated: Mar 11, 2023 |
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Pathogenic
(Aug 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024955.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000961403.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33971440, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as "IVS1-1 G-T". ClinVar contains an entry for this variant (Variation ID: 15437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 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: SCV000603902.9
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The HBB c.92+1G>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with … (more)
The HBB c.92+1G>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia (see HbVar link, Kazazian 1984); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Kazazian HH Jr et al. (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 3(3):593-6. PMID: 6714226 (less)
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Pathogenic
(Aug 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002682236.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was … (more)
The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was reported in an infant with beta thalassemia major in conjunction with a second HBB alteration (Garewal G et al. Am. J. Hematol., 2005 Aug;79:252-6). This mutation is a common cause of beta thalassenia and results in beta-zero thalassemia (Chan OT et al. Am. J. Clin. Pathol., 2010 May;133:700-7; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(May 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854929.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
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Pathogenic
(Feb 27, 2017)
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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
|
OMIM
Accession: SCV000036965.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 02, 2017 |
Comment on evidence:
Splice junction mutant, G to T, at position 1 of IVS1 was found in an Asian Indian and in Chinese by Kazazian et al. (1984).
|
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Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244437.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
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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: SCV002091589.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(May 07, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: yes
Allele origin:
germline
|
MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN
Accession: SCV005186152.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe … (more)
The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] (less)
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Southeast Asian
Geographic origin: India
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Pathogenic
(Dec 22, 2023)
|
no assertion criteria provided
Method: clinical testing
|
HBB-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004739777.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, … (more)
The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, has been reported to be causative for beta-thalassemia with highest frequencies for the variant being found in Indian and Thai populations (Edison et al. 2008. PubMed ID: 18294253; Muhammad et al. 2017. PubMed ID: 28635337; Kazazian et al 1984. PubMed ID: 6714226; http://ccg.murdoch.edu.au/thalind/variants.php). Another substitution at the same position, c.92+1G>A, has also been found in individuals with beta-thalassemia (Faustino et al. 1992. PubMed ID: 1634236; Waye et al. 2002. PubMed ID: 11939519). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in HBB are expected to be pathogenic. The c.92G>T variant is interpreted as pathogenic. (less)
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Citation text
Kazazian, H. H., Jr. Personal Communication. 1982. Baltimore, Md.
Comment:
Variant summary: HBB c.92+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 7.2e-05 in 251366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (7.2e-05 vs 0.011), allowing no conclusion about variant significance. c.92+1G>T has been reported in the literature in numerous individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8199027, 16044458, 10975438, 2064964, 26865073, 26715484, 26554253, 22975760, 25525159, 10870879, 9225979, 18294253, 26291967, 12885342, 19090545, 18759082, 19000664, 19843386, 19254853, 28635337, 6714226, 27263053, 30275481, 9629495, 31890591, 9163586, 8012089)
Comment:
This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33971440, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as "IVS1-1 G-T". ClinVar contains an entry for this variant (Variation ID: 15437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The HBB c.92+1G>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia (see HbVar link, Kazazian 1984); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Kazazian HH Jr et al. (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 3(3):593-6. PMID: 6714226
Comment:
The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was reported in an infant with beta thalassemia major in conjunction with a second HBB alteration (Garewal G et al. Am. J. Hematol., 2005 Aug;79:252-6). This mutation is a common cause of beta thalassenia and results in beta-zero thalassemia (Chan OT et al. Am. J. Clin. Pathol., 2010 May;133:700-7; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018]
Comment:
The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, has been reported to be causative for beta-thalassemia with highest frequencies for the variant being found in Indian and Thai populations (Edison et al. 2008. PubMed ID: 18294253; Muhammad et al. 2017. PubMed ID: 28635337; Kazazian et al 1984. PubMed ID: 6714226; http://ccg.murdoch.edu.au/thalind/variants.php). Another substitution at the same position, c.92+1G>A, has also been found in individuals with beta-thalassemia (Faustino et al. 1992. PubMed ID: 1634236; Waye et al. 2002. PubMed ID: 11939519). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in HBB are expected to be pathogenic. The c.92G>T variant is interpreted 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: HBB c.92+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 7.2e-05 in 251366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (7.2e-05 vs 0.011), allowing no conclusion about variant significance. c.92+1G>T has been reported in the literature in numerous individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8199027, 16044458, 10975438, 2064964, 26865073, 26715484, 26554253, 22975760, 25525159, 10870879, 9225979, 18294253, 26291967, 12885342, 19090545, 18759082, 19000664, 19843386, 19254853, 28635337, 6714226, 27263053, 30275481, 9629495, 31890591, 9163586, 8012089)
Comment:
This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33971440, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as "IVS1-1 G-T". ClinVar contains an entry for this variant (Variation ID: 15437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The HBB c.92+1G>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia (see HbVar link, Kazazian 1984); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Kazazian HH Jr et al. (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 3(3):593-6. PMID: 6714226
Comment:
The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was reported in an infant with beta thalassemia major in conjunction with a second HBB alteration (Garewal G et al. Am. J. Hematol., 2005 Aug;79:252-6). This mutation is a common cause of beta thalassenia and results in beta-zero thalassemia (Chan OT et al. Am. J. Clin. Pathol., 2010 May;133:700-7; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018]
Comment:
The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, has been reported to be causative for beta-thalassemia with highest frequencies for the variant being found in Indian and Thai populations (Edison et al. 2008. PubMed ID: 18294253; Muhammad et al. 2017. PubMed ID: 28635337; Kazazian et al 1984. PubMed ID: 6714226; http://ccg.murdoch.edu.au/thalind/variants.php). Another substitution at the same position, c.92+1G>A, has also been found in individuals with beta-thalassemia (Faustino et al. 1992. PubMed ID: 1634236; Waye et al. 2002. PubMed ID: 11939519). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in HBB are expected to be pathogenic. The c.92G>T variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype correlation among beta-thalassemia and beta-thalassemia/HbE disease in Thai children: predictable clinical spectrum using genotypic analysis. | Traivaree C | Journal of blood medicine | 2018 | PMID: 29695942 |
| Population-Based Genetic Study of β-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan. | Muhammad R | Hemoglobin | 2017 | PMID: 28635337 |
| The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. | Yasmeen H | European journal of medical genetics | 2016 | PMID: 27263053 |
| Non-Invasive DNA Sampling for Molecular Analysis of Beta-Thalassemia: Amiable Alternative Sampling Methods with Accurate Results for Pediatric Patients. | Abd Rahim MR | Clinical laboratory | 2015 | PMID: 26554253 |
| Genotype-phenotype correlation and report of novel mutations in β-globin gene in thalassemia patients. | Nagar R | Blood cells, molecules & diseases | 2015 | PMID: 25976460 |
| Genetic heterogeneity of the β-globin gene in various geographic populations of Yunnan in southwestern China. | Zhang J | PloS one | 2015 | PMID: 25849334 |
| The molecular basis of β-thalassemia. | Thein SL | Cold Spring Harbor perspectives in medicine | 2013 | PMID: 23637309 |
| Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia. | Sivalingam M | International journal of laboratory hematology | 2012 | PMID: 22335963 |
| 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 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Nucleotide -88 (C-T) promoter mutation is a common beta-thalassemia mutation in the Jat Sikhs of Punjab, India. | Garewal G | American journal of hematology | 2005 | PMID: 16044458 |
| Beta-thalassaemia intermedia: is it possible consistently to predict phenotype from genotype? | Ho PJ | British journal of haematology | 1998 | PMID: 9450794 |
| The molecular basis of beta thalassaemia in Punjabi and Maharashtran Indians includes a multilocus aetiology involving triplicated alpha-globin loci. | Garewal G | British journal of haematology | 1994 | PMID: 8199027 |
| Molecular characterization of seven beta-thalassemia mutations in Asian Indians. | Kazazian HH Jr | The EMBO journal | 1984 | PMID: 6714226 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HBB | - | - | - | - |
| https://ithanet.eu/db/ithagenes?ithaID=102 | - | - | - | - |
| Kazazian, H. H., Jr. Personal Communication. 1982. Baltimore, Md. | - | - | - | - |
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Record last updated Nov 10, 2024
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