VCV000015438.125 - ClinVar

NM_000518.5(HBB):c.315+1G>A

Germline

Classification

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.

(25)

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

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.315+1G>A

Variation ID: 15438 Accession: VCV000015438.125

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 5226576 (GRCh38) [ NCBI UCSC ] 11: 5247806 (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	Oct 9, 2016	Jun 17, 2024	Mar 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000518.5:c.315+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000011.10:g.5226576C>T
NC_000011.9:g.5247806C>T
NG_000007.3:g.71040G>A
NG_042296.1:g.107C>T
NG_046672.1:g.4511C>T
NG_053049.1:g.2897C>T
NG_059281.1:g.5496G>A
LRG_1232:g.5496G>A
LRG_1232t1:c.315+1G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS2-1G>A
IVS-2-1G>A
IVS II-1 G>A
IVS2, G-A, +1

Canonical SPDI

NC_000011.10:5226575:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00012

Links

dbSNP: rs33945777 HBVAR: 884 ClinGen: CA125305 Genetic Testing Registry (GTR): GTR000500319 Genetic Testing Registry (GTR): GTR000556525 OMIM: 141900.0348 VarSome

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
Gene	OMIM	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	1835
LOC106099062	-	-	-	GRCh38	-	863
LOC107133510	-	-	-	GRCh38	-	1785
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.
beta Thalassemia	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Nov 3, 2022	RCV000020332.25
Beta zero thalassemia	Pathogenic (2)	no assertion criteria provided	Jan 1, 2018	RCV000016696.37
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000255349.35
Hb SS disease	Pathogenic (1)	criteria provided, single submitter	-	RCV001004566.9
Dominant beta-thalassemia	Pathogenic (1)	criteria provided, single submitter	Aug 18, 2021	RCV001723572.9
not specified	Pathogenic (1)	criteria provided, single submitter	May 14, 2020	RCV001731303.12
Beta-thalassemia HBB/LCRB	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV002288502.10
Beta-thalassemia HBB/LCRB Dominant beta-thalassemia Erythrocytosis, familial, 6 Hb SS disease Heinz body anemia Hereditary persistence of fetal hemoglobin METHEMOGLOBINEMIA, BETA TYPE Malaria, susceptibility to alpha Thalassemia	Pathogenic (1)	criteria provided, single submitter	Jan 13, 2022	RCV002476979.8
Malaria, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Mar 17, 2024	RCV003987325.3

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.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hb SS disease Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163650.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426506.1 First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020	Publications: PubMed (1) PubMed: 32860008
Pathogenic (Sep 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520749.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Feb 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581299.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3, PS4_MOD, PM3, PM2_SUP, PP4	Number of individuals with the variant: 2 Sex: male
Pathogenic (Jan 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000893886.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000958500.6 First in ClinVar: Aug 13, 2019 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 2446680‚ 23590658‚ 25332589‚ 27263053‚ 28391758‚ 17576681‚ 9536098‚ 7151176 Comment: This sequence change affects a donor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs33945777, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with HBB-related conditions (PMID: 2446680, 23590658, 25332589, 27263053, 28391758). This variant is also known as IVS-II-1 (G>A). ClinVar contains an entry for this variant (Variation ID: 15438). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in insertion of the first 47 nucleotides of intron 2 between exons 2 and 3 or with exon 2 skipping and introduces a new termination codon (PMID: 7151176). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603893.9 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The HBB c.315+1G>A variant (rs33945777, HbVar ID: 884), also known as IVS-II-1 G>A, has been identified in multiple patients with beta-0 thalassemia in both the … (more) The HBB c.315+1G>A variant (rs33945777, HbVar ID: 884), also known as IVS-II-1 G>A, has been identified in multiple patients with beta-0 thalassemia in both the homozygous state and in heterozygotes with a second pathogenic HBB variant (Jalilian 2017, Oppenheim 1990, Treisman 1982, Wong 1986, HbVar database). This variant abolishes the canonical splice donor site of intron 2, and functional characterization indicates the absence of normally spliced transcripts and generation of small amounts of aberrantly spliced mRNA (Treisman 1982, Treisman 1983), consistent with computational predictions (Alamut v.2.11). The variant is reported as pathogenic in ClinVar (Variation ID: 15438) and is found in the general population with an overall allele frequency of 0.004% (11/282562 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jalilian M et al. The Frequency of HBB Mutations Among ß-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Oppenheim A et al. Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant. Hum Genet. 1990 Dec;86(2):175-80. PMID: 1702403. Treisman R et al. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903-11. PMID: 7151176 Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. PMID: 6188062. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6529-32. PMID: 3462712. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Beta-thalassemia HBB/LCRB Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051811.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (May 03, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	beta Thalassemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697106.1 First in ClinVar: Mar 22, 2017 Last updated: Mar 22, 2017	Publications: PubMed (5) PubMed: 12144057‚ 2446680‚ 15654898‚ 7151176‚ 25525159 Comment: Variant summary: The HBB c.315+1G>A variant affects a conserved nucleotide located in a canonical splice-site. Mutation taster predicts damaging outcome for this variant along with … (more) Variant summary: The HBB c.315+1G>A variant affects a conserved nucleotide located in a canonical splice-site. Mutation taster predicts damaging outcome for this variant along with 5/5 splice-tools via Alamut predicting this variant to completely abolish 5' splicing donor site. These predictions have been confirmed by a functional study (Treisman_1982) suggesting pathogenicity. The variant was found in 5/121204 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected frequency of a pathogenic HBB allele (0.0111803). Moreover, it was reported in several patients with BTHAL and thalassemia major further supporting pathogenicity. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	beta Thalassemia Affected status: unknown Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000746439.1 First in ClinVar: Mar 22, 2017 Last updated: Mar 22, 2017	Number of individuals with the variant: 2 Age: 20-29 years Sex: female Geographic origin: Iran
Pathogenic (Dec 04, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193967.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (4) PubMed: 1483699‚ 25332589‚ 7558878‚ 1634368 Comment: NM_000518.4(HBB):c.315+1G>A is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero … (more) NM_000518.4(HBB):c.315+1G>A is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 1483699, 25332589, 7558878 and 1634368. Classification of NM_000518.4(HBB):c.315+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Jul 22, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Beta-thalassemia HBB/LCRB Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001810475.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Sex: mixed
Pathogenic (Aug 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dominant beta-thalassemia Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950085.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Comment: This variant was identified as homozygous.
Pathogenic (May 14, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital Accession: SCV001984020.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 Comment: The c.315+1G>A variant in HBB is a well established Beta-zero thalassmia allele leading to complete inactivation of the HBB gene (HbVar database). It has been … (more) The c.315+1G>A variant in HBB is a well established Beta-zero thalassmia allele leading to complete inactivation of the HBB gene (HbVar database). It has been observed in 11/282562 (0.004% 0 homozygotes) total alleles in the Genome aggregation database (gbnomAD). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Experimental studies have shown that this variant has a deleterious effect on splicing (PMID: 7151176). In summary this variant meets our criteria to be classified as pathogenic . (less)
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321763.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported previously in association with beta-thalassemia and reported to … (more) Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported previously in association with beta-thalassemia and reported to result in abnormal RNA splicing (Nasouhipur et al., 2014; Poddighe et al., 2015; Treisman et al., 1982); This variant is associated with the following publications: (PMID: 25087612, 25525159, 25332589, 26193974, 7151176, 28391758, 32581362, 34272389, 11559936, 34426522, 9163586, 8091935, 31589614, 14555304) (less)
Pathogenic (Nov 24, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601271.3 First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024	Publications: PubMed (6) PubMed: 28391758‚ 25332589‚ 27263053‚ 7151176‚ 3462712‚ 26193974 Comment: The HBB c.315+1G>A pathogenic variant disrupts a canonical splice-donor site and interferes with normal splicing of the beta globin mRNA. The variant is associated with … (more) The HBB c.315+1G>A pathogenic variant disrupts a canonical splice-donor site and interferes with normal splicing of the beta globin mRNA. The variant is associated with beta-zero thalassemia (, and PMID: 28391758 (2017), 26193974 (2015), 25332589 (2014), 7151176 (1982)). (less)
Pathogenic (Mar 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024958.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 17, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Malaria, susceptibility to Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004804905.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	beta Thalassemia Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847540.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The c.315+1G>A variant in HBB, also known as IVS-II-1 G>A, has been identified in multiple individuals with beta-thalassemia in both the homozygous and in the … (more) The c.315+1G>A variant in HBB, also known as IVS-II-1 G>A, has been identified in multiple individuals with beta-thalassemia in both the homozygous and in the compound heterozygous state (Jalilian 2017 PMID: 28391758, Wakamatsu 1994 PMID: 8091935, Treisman 1982 PMID: 7151176, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=884). It has been reported in ClinVar (Variation ID 15438)and has been identified in 7/41440 African chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3. (less)
Pathogenic (Mar 15, 1998)	no assertion criteria provided Method: literature only	BETA-ZERO-THALASSEMIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036966.2 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (7) PubMed: 7151176‚ 3422218‚ 2903765‚ 1634368‚ 1427786‚ 8917506‚ 9490703 Comment on evidence: A splice junction mutant, G to A, at position 1 of IVS2 was found in a Mediterranean by Treisman et al. (1982), in a Tunisian … (more) A splice junction mutant, G to A, at position 1 of IVS2 was found in a Mediterranean by Treisman et al. (1982), in a Tunisian by Chibani et al. (1988), and in an American black by Thein et al. (1988). The same mutation was found by Hattori et al. (1992), who referred to the mutation as IVS2-1 (G-A). This is one of the earliest mutations at a 5-prime splice site to be described. In an analysis of 101 different examples of point mutations that lie in the vicinity of mRNA splice junctions and that have been held to be responsible for human genetic disease by altering the accuracy or efficiency of mRNA splicing, Krawczak et al. (1992) found that 62 were located at 5-prime splice sites, 26 at 3-prime splice sites, and 13 resulted in the creation of novel splice sites. They estimated that up to 15% of all point mutations causing human genetic disease result in an mRNA splicing defect. Of the 5-prime splice site mutations, 60% involve the invariant GT dinucleotides. Sierakowska et al. (1996) found that treatment of mammalian cells stably expressing the IVS2-654 beta HBB gene with antisense oligonucleotides targeted at the aberrant splice sites restored correct splicing in a dose-dependent fashion, generating correct human beta-globin mRNA and polypeptide. Both products persisted for up to 72 hours after treatment. The oligonucleotides modified splicing by a true antisense mechanism without overt unspecific effects on cell growth and splicing of other pre-mRNAs. Sierakowska et al. (1996) stated that this novel approach in which antisense oligonucleotides are used to restore rather than to downregulate the activity of the target gene is applicable to other splicing mutants and is of potential clinical interest. This mutation is frequent among patients in southern China and Thailand, accounting for 20% of beta-thalassemia in some regions. It causes aberrant RNA splicing. Lewis et al. (1998) modeled this mutation in mice, replacing the 2 (cis) murine adult beta-globin genes with a single copy of the human mutant HBB gene. No homozygous mice survived postnatally. Heterozygous mice carrying this mutant gene produced reduced amounts of mouse beta-globin chains and no human beta globin, and had a moderately severe form of beta-thalassemia. Heterozygotes showed the same aberrant splicing as their human counterparts and provided an animal model for testing therapies that correct splicing defects at either the RNA or DNA level. (less)
Pathogenic (Jan 01, 2018)	no assertion criteria provided Method: research	beta^0^ Thalassemia Affected status: yes Allele origin: germline	College of Science, Al Muthanna University, Al Muthanna University Accession: SCV000864069.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Publications: PubMed (1) PubMed: 31714438 Age: 8-25 years Sex: mixed Ethnicity/Population group: Arabic Iraqi Geographic origin: Iraq
Pathogenic (-)	no assertion criteria provided Method: research	Beta-thalassemia HBB/LCRB Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162252.1 First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: female
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: SCV001244636.1 First in ClinVar: Apr 24, 2020 Last updated: Apr 24, 2020	Publications: PubMed (3) PubMed: 6270663‚ 7151176‚ 27263053 Other databases https://ithanet.eu/db/ithagenes?… https://ithanet.eu/db/ithagenes?ithaID=200
Pathogenic (Mar 17, 2017)	no assertion criteria provided Method: clinical testing	Beta thalassemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089197.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
not provided (-)	no classification provided Method: literature only	beta Thalassemia Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040708.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1426 BookShelf: NBK1426
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Comment:

This sequence change affects a donor splice site in intron 2 of the HBB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs33945777, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with HBB-related conditions (PMID: 2446680, 23590658, 25332589, 27263053, 28391758). This variant is also known as IVS-II-1 (G>A). ClinVar contains an entry for this variant (Variation ID: 15438). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in insertion of the first 47 nucleotides of intron 2 between exons 2 and 3 or with exon 2 skipping and introduces a new termination codon (PMID: 7151176). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Comment:

The HBB c.315+1G>A variant (rs33945777, HbVar ID: 884), also known as IVS-II-1 G>A, has been identified in multiple patients with beta-0 thalassemia in both the homozygous state and in heterozygotes with a second pathogenic HBB variant (Jalilian 2017, Oppenheim 1990, Treisman 1982, Wong 1986, HbVar database). This variant abolishes the canonical splice donor site of intron 2, and functional characterization indicates the absence of normally spliced transcripts and generation of small amounts of aberrantly spliced mRNA (Treisman 1982, Treisman 1983), consistent with computational predictions (Alamut v.2.11). The variant is reported as pathogenic in ClinVar (Variation ID: 15438) and is found in the general population with an overall allele frequency of 0.004% (11/282562 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Jalilian M et al. The Frequency of HBB Mutations Among ß-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Oppenheim A et al. Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant. Hum Genet. 1990 Dec;86(2):175-80. PMID: 1702403. Treisman R et al. A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing. Cell. 1982 Jul;29(3):903-11. PMID: 7151176 Treisman R et al. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591-6. PMID: 6188062. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6529-32. PMID: 3462712.

Comment:

Variant summary: The HBB c.315+1G>A variant affects a conserved nucleotide located in a canonical splice-site. Mutation taster predicts damaging outcome for this variant along with 5/5 splice-tools via Alamut predicting this variant to completely abolish 5' splicing donor site. These predictions have been confirmed by a functional study (Treisman_1982) suggesting pathogenicity. The variant was found in 5/121204 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected frequency of a pathogenic HBB allele (0.0111803). Moreover, it was reported in several patients with BTHAL and thalassemia major further supporting pathogenicity. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_000518.4(HBB):c.315+1G>A is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 1483699, 25332589, 7558878 and 1634368. Classification of NM_000518.4(HBB):c.315+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Reported previously in association with beta-thalassemia and reported to result in abnormal RNA splicing (Nasouhipur et al., 2014; Poddighe et al., 2015; Treisman et al., 1982); This variant is associated with the following publications: (PMID: 25087612, 25525159, 25332589, 26193974, 7151176, 28391758, 32581362, 34272389, 11559936, 34426522, 9163586, 8091935, 31589614, 14555304)

Comment:

The HBB c.315+1G>A pathogenic variant disrupts a canonical splice-donor site and interferes with normal splicing of the beta globin mRNA. The variant is associated with beta-zero thalassemia (, and PMID: 28391758 (2017), 26193974 (2015), 25332589 (2014), 7151176 (1982)).

Comment:

The c.315+1G>A variant in HBB, also known as IVS-II-1 G>A, has been identified in multiple individuals with beta-thalassemia in both the homozygous and in the compound heterozygous state (Jalilian 2017 PMID: 28391758, Wakamatsu 1994 PMID: 8091935, Treisman 1982 PMID: 7151176, https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=884). It has been reported in ClinVar (Variation ID 15438)and has been identified in 7/41440 African chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Beta-Thalassemia.	Adam MP	-	2024	PMID: 20301599
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Clinical Laboratory Manifestation and Molecular Diagnosis of β-Thalassemia Patients in Iraq.	AlMosawi RHN	Journal of pediatric hematology/oncology	2020	PMID: 31714438
The Frequency of HBB Mutations Among β-Thalassemia Patients in Hamadan Province, Iran.	Jalilian M	Hemoglobin	2017	PMID: 28391758
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
β-Thalassemia Intermedia Associated with Heterozygous and Isolate β-Globin Gene Mutation [IVS-II-1 (HBB: c.315G>A)].	Poddighe D	Hemoglobin	2015	PMID: 26193974
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Hb Knossos: HBB:c.82G>T Associated with HBB:c.315+1G>A Beta Zero Mutation Causes Thalassemia Intermedia.	Nasouhipur H	Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion	2014	PMID: 25332589
Prenatal and newborn screening for hemoglobinopathies.	Hoppe CC	International journal of laboratory hematology	2013	PMID: 23590658
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Serum ferritin level as a predictor of impaired growth and puberty in thalassemia major patients.	Shalitin S	European journal of haematology	2005	PMID: 15654898
Beta-thalassemia intermedia from southern Iran: IVS-II-1 (G-->A) is the prevalent thalassemia intermedia allele.	Karimi M	Hemoglobin	2002	PMID: 12144057
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
A common human beta globin splicing mutation modeled in mice.	Lewis J	Blood	1998	PMID: 9490703
Repair of thalassemic human beta-globin mRNA in mammalian cells by antisense oligonucleotides.	Sierakowska H	Proceedings of the National Academy of Sciences of the United States of America	1996	PMID: 8917506
A newly discovered beta O-thalassemia (IVS-II-850, G-->A) mutation in a north European family.	Cürük MA	Hemoglobin	1995	PMID: 7558878
Three beta-thalassemia mutations in the Japanese: IVS-II-1 (G----A), IVS-II-848 (C----G), and codon 90 (GAG----TAG).	Hattori Y	Hemoglobin	1992	PMID: 1634368
Molecular characterization of beta-thalassemia in Azerbaijan.	Cürük MA	Human genetics	1992	PMID: 1483699
The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences.	Krawczak M	Human genetics	1992	PMID: 1427786
The peculiar spectrum of beta-thalassemia genes in Tunisia.	Chibani J	Human genetics	1988	PMID: 3422218
The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis.	Thein SL	British journal of haematology	1988	PMID: 2903765
Mild and severe beta-thalassemia among homozygotes from Turkey: identification of the types by hybridization of amplified DNA with synthetic probes.	Diaz-Chico JC	Blood	1988	PMID: 2446680
On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups.	Wong C	Proceedings of the National Academy of Sciences of the United States of America	1986	PMID: 3462712
A single-base change at a splice site in a beta 0-thalassemic gene causes abnormal RNA splicing.	Treisman R	Cell	1982	PMID: 7151176
A nucleotide change at a splice junction in the human beta-globin gene is associated with beta 0-thalassemia.	Baird M	Proceedings of the National Academy of Sciences of the United States of America	1981	PMID: 6270663
https://ithanet.eu/db/ithagenes?ithaID=200	-	-	-	-
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Text-mined citations for rs33945777 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000518.5(HBB):c.315+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs33945777 ...