The c.316-146T>G variant (also known as IVS-II-705 (T->G), rs35328027, HbVar ID: 890) has been reported in a patient diagnosed with beta(+) thalassemia (Spence 1982). This variant is reported in ClinVar (Variation ID: 36312) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Functional characterization of the mRNA transcript indicate that the variant causes the utilization of a cryptic splice acceptor 126 nucleotides upstream, leading to the inclusion of sequences from intron 2 of HBB (Dobkin 1983). Based on the above information, the variant is classified as pathogenic. References: HbVar link: https://globin.bx.psu.edu/hbvar/hbvar.html Dobkin C et al. Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. Proc Natl Acad Sci U S A. 1983. 80(5):1184-8. PMID: 6298782. Spence S et al. Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient. Nucleic Acids Res. 1982. 10(4):1283-94. PMID: 6280138.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.316-146T>G
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.
(5)
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
5
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.316-146T>G
Variation ID: 36312 Accession: VCV000036312.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225872 (GRCh38) [ NCBI UCSC ] 11: 5247102 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Jan 6, 2024 Aug 29, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.316-146T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.5225872A>C NC_000011.9:g.5247102A>C NG_000007.3:g.71744T>G NG_046672.1:g.3807A>C NG_053049.1:g.2193A>C NG_059281.1:g.6200T>G LRG_1232:g.6200T>G LRG_1232t1:c.316-146T>G - Protein change
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- Other names
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IVS II-705 (T>G)
IVS2, T-G, +705
- Canonical SPDI
- NC_000011.10:5225871:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
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 | |
| 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
|
Mar 1, 1983 | RCV000016714.32 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Feb 12, 2018 | RCV000029979.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2023 | RCV000985748.13 |
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
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603919.3
First in ClinVar: Sep 30, 2017 Last updated: Mar 04, 2023 |
Comment:
The c.316-146T>G variant (also known as IVS-II-705 (T->G), rs35328027, HbVar ID: 890) has been reported in a patient diagnosed with beta(+) thalassemia (Spence 1982). This … (more)
The c.316-146T>G variant (also known as IVS-II-705 (T->G), rs35328027, HbVar ID: 890) has been reported in a patient diagnosed with beta(+) thalassemia (Spence 1982). This variant is reported in ClinVar (Variation ID: 36312) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Functional characterization of the mRNA transcript indicate that the variant causes the utilization of a cryptic splice acceptor 126 nucleotides upstream, leading to the inclusion of sequences from intron 2 of HBB (Dobkin 1983). Based on the above information, the variant is classified as pathogenic. References: HbVar link: https://globin.bx.psu.edu/hbvar/hbvar.html Dobkin C et al. Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. Proc Natl Acad Sci U S A. 1983. 80(5):1184-8. PMID: 6298782. Spence S et al. Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient. Nucleic Acids Res. 1982. 10(4):1283-94. PMID: 6280138. (less)
|
|
|
Pathogenic
(Feb 12, 2018)
|
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: SCV000052634.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 11, 2022 |
Comment:
Variant summary: HBB c.316-146T>G (Legacy Name: IVS-II-705 (T->G)) is located at a position not widely known to affect splicing. However, several computational tools predict a … (more)
Variant summary: HBB c.316-146T>G (Legacy Name: IVS-II-705 (T->G)) is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site and one predicts the variant creates a 3' acceptor site. Gorman_1998 states "In the thalassemic IVS2705 human b-globin gene, a T-to-G mutation at position 705 of intron 2 improves the match of the surrounding sequence to the consensus donor splice site (ACTGAT/GTAAGA to ACTGAG/GTAAGA; / indicates the splice site). In the transcribed IVS2705 pre-mRNA, the presence of this new 5' splice site activates an acceptor splice site 126 nt upstream, resulting in incorrectly spliced b-globin mRNA containing a fragment of the intron (Fig. 1A). This fragment creates a premature stop codon resulting in a truncated b-globin polypeptide." Multiple functional studies support these predictions (Dobkin_1983, Spenc_1982, and Gorman_1998). The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.316-146T>G, has been reported in the literature in individuals affected with Beta Thalassemia Intermedia. These data indicate that the variant may be associated with disease. A ClinVar submission (evaluation after 2014) from a clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134226.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
The HBB c.316-146T>G variant has been reported in the published literature in individuals with beta-thalassemia trait (PMID: 29251008 (2018)) and in trans with another pathogenic … (more)
The HBB c.316-146T>G variant has been reported in the published literature in individuals with beta-thalassemia trait (PMID: 29251008 (2018)) and in trans with another pathogenic HBB variant in an individual with beta(+) thalassemia (PMID: 30843739 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Mar 01, 1983)
|
no assertion criteria provided
Method: literature only
|
BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036984.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
A T-to-G change at position 705 of IVS2 was found in a Mediterranean patient with beta-plus-thalassemia (613985) by Dobkin et al. (1983). The mutation created … (more)
A T-to-G change at position 705 of IVS2 was found in a Mediterranean patient with beta-plus-thalassemia (613985) by Dobkin et al. (1983). The mutation created a new acceptor splice site. (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: SCV001244412.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
Comment:
Comment:
Variant summary: HBB c.316-146T>G (Legacy Name: IVS-II-705 (T->G)) is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site and one predicts the variant creates a 3' acceptor site. Gorman_1998 states "In the thalassemic IVS2705 human b-globin gene, a T-to-G mutation at position 705 of intron 2 improves the match of the surrounding sequence to the consensus donor splice site (ACTGAT/GTAAGA to ACTGAG/GTAAGA; / indicates the splice site). In the transcribed IVS2705 pre-mRNA, the presence of this new 5' splice site activates an acceptor splice site 126 nt upstream, resulting in incorrectly spliced b-globin mRNA containing a fragment of the intron (Fig. 1A). This fragment creates a premature stop codon resulting in a truncated b-globin polypeptide." Multiple functional studies support these predictions (Dobkin_1983, Spenc_1982, and Gorman_1998). The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.316-146T>G, has been reported in the literature in individuals affected with Beta Thalassemia Intermedia. These data indicate that the variant may be associated with disease. A ClinVar submission (evaluation after 2014) from a clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The HBB c.316-146T>G variant has been reported in the published literature in individuals with beta-thalassemia trait (PMID: 29251008 (2018)) and in trans with another pathogenic HBB variant in an individual with beta(+) thalassemia (PMID: 30843739 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is 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:
The c.316-146T>G variant (also known as IVS-II-705 (T->G), rs35328027, HbVar ID: 890) has been reported in a patient diagnosed with beta(+) thalassemia (Spence 1982). This variant is reported in ClinVar (Variation ID: 36312) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Functional characterization of the mRNA transcript indicate that the variant causes the utilization of a cryptic splice acceptor 126 nucleotides upstream, leading to the inclusion of sequences from intron 2 of HBB (Dobkin 1983). Based on the above information, the variant is classified as pathogenic. References: HbVar link: https://globin.bx.psu.edu/hbvar/hbvar.html Dobkin C et al. Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. Proc Natl Acad Sci U S A. 1983. 80(5):1184-8. PMID: 6298782. Spence S et al. Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient. Nucleic Acids Res. 1982. 10(4):1283-94. PMID: 6280138.
Comment:
Variant summary: HBB c.316-146T>G (Legacy Name: IVS-II-705 (T->G)) is located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Three predict the variant strengthens a cryptic 5' donor site and one predicts the variant creates a 3' acceptor site. Gorman_1998 states "In the thalassemic IVS2705 human b-globin gene, a T-to-G mutation at position 705 of intron 2 improves the match of the surrounding sequence to the consensus donor splice site (ACTGAT/GTAAGA to ACTGAG/GTAAGA; / indicates the splice site). In the transcribed IVS2705 pre-mRNA, the presence of this new 5' splice site activates an acceptor splice site 126 nt upstream, resulting in incorrectly spliced b-globin mRNA containing a fragment of the intron (Fig. 1A). This fragment creates a premature stop codon resulting in a truncated b-globin polypeptide." Multiple functional studies support these predictions (Dobkin_1983, Spenc_1982, and Gorman_1998). The variant was absent in 30972 control chromosomes (gnomAD). The variant, c.316-146T>G, has been reported in the literature in individuals affected with Beta Thalassemia Intermedia. These data indicate that the variant may be associated with disease. A ClinVar submission (evaluation after 2014) from a clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The HBB c.316-146T>G variant has been reported in the published literature in individuals with beta-thalassemia trait (PMID: 29251008 (2018)) and in trans with another pathogenic HBB variant in an individual with beta(+) thalassemia (PMID: 30843739 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| First Report on the Coinheritance of α-Thalassemia and a Rare β-Thalassemia Compound Heterozygosity for the IVS-I-I(G>A)/IVS-II-705(T>G) Mutations in a Syrian Family. | Murad H | Hemoglobin | 2019 | PMID: 30843739 |
| First Report of the Rare IVS-II-705 (T>G) β-Thalassemia Mutation in a Chinese Family. | Jiang F | Hemoglobin | 2017 | PMID: 29251008 |
| Hb A(1c) Determination by Capillary Electrophoresis is an Efficient Method for Detecting β-Thalassemias and Hemoglobin Variants. | Orts JA | Hemoglobin | 2016 | PMID: 27535164 |
| Coinheritance of a Rare Nucleotide Substitution on the β-Globin Gene and Other Known Mutations in the Globin Clusters: Management in Genetic Counseling. | Vinciguerra M | Hemoglobin | 2016 | PMID: 27258795 |
| Identification of three new nucleotide substitutions in the β-globin gene: laboratoristic approach and impact on genetic counselling for beta-thalassaemia. | Vinciguerra M | European journal of haematology | 2014 | PMID: 24401016 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| Effect of co-inheritance of β-thalassemia and hemochromatosis mutations on iron overload. | López-Escribano H | Hemoglobin | 2012 | PMID: 22122796 |
| 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 |
| 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 |
| Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs. | Gorman L | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9560205 |
| Determination of the spectrum of beta-thalassemia genes in Spain by use of dot-blot analysis of amplified beta-globin DNA. | Amselem S | American journal of human genetics | 1988 | PMID: 2897787 |
| Abnormal splice in a mutant human beta-globin gene not at the site of a mutation. | Dobkin C | Proceedings of the National Academy of Sciences of the United States of America | 1983 | PMID: 6298782 |
| Five nucleotide changes in the large intervening sequence of a beta globin gene in a beta+ thalassemia patient. | Spence SE | Nucleic acids research | 1982 | PMID: 6280138 |
| https://ithanet.eu/db/ithagenes?ithaID=212 | - | - | - | - |
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Text-mined citations for rs35328027 ...
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 10, 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.