ClinVar Genomic variation as it relates to human health
NM_005142.3(CBLIF):c.79+1G>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005142.3(CBLIF):c.79+1G>A
Variation ID: 439755 Accession: VCV000439755.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q12.1 11: 59845374 (GRCh38) [ NCBI UCSC ] 11: 59612847 (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 Apr 4, 2013 Feb 20, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005142.3:c.79+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000011.10:g.59845374C>T NC_000011.9:g.59612847C>T NG_008120.1:g.5128G>A - Protein change
- Other names
- IVS1DS, G-A, +1
- Canonical SPDI
- NC_000011.10:59845373:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00020
Exome Aggregation Consortium (ExAC) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00022
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CBLIF | - | - |
GRCh38 GRCh37 |
145 | 154 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV000688054.27 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Jun 3, 2019 | RCV001197357.10 |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2020 | RCV000734690.17 |
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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Pathogenic
(Aug 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000862849.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary intrinsic factor deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915532.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GIF c.79+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant … (more)
The GIF c.79+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in four studies in which it is found in a total of 13 individuals with intrinsic factor deficiency, megaloblastic anemia and cobalamin malabsorption. The variant was reported in a homozygous state in four individuals, including three unrelated cases and in a compound heterozygous state in nine individuals, six of whom were unrelated (Tanner et al. 2005; Overgaard et al. 2010; Tanner et al. 2012; Ferrand et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence and the potential impact of splice donor variants, the c.79+1G>A variant is classified as pathogenic for intrinsic factor deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Congenital intrinsic factor deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966891.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
The c.79+1G>A variant in GIF (also referred to as CBLIF) has been reported in at least 7 compound heterozygous and 4 homozygous individuals with intrinsic … (more)
The c.79+1G>A variant in GIF (also referred to as CBLIF) has been reported in at least 7 compound heterozygous and 4 homozygous individuals with intrinsic facto r deficiency and segregated with disease in 2 affected relatives from 2 families (Ferrand 2015, Overgaard 2010, Stray-Pedersen 2017, Tanner 2005, Tanner 2012). It has also been identified in 0.03% (41/28970) of European chromosomes by gnomA D (http://gnomad.broadinstitute.org). This variant has also been reported in Cli nVar (Variation ID 439755). 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 GIF gene is an established disease mecha nism in autosomal recessive intrinsic factor deficiency. In summary, this varian t meets criteria to be classified as pathogenic for autosomal recessive intrinsi c factor deficiency. ACMG/AMP Criteria applied: PM3_Strong, PVS1_Strong. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary intrinsic factor deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149783.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(Jun 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368065.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PM3.
Clinical Features:
Hypertelorism (present) , Low-set ears (present) , Downslanted palpebral fissures (present) , Global developmental delay (present) , Generalized hypotonia (present)
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Pathogenic
(Feb 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603809.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021 |
Comment:
The CBLIF c.79+1G>A variant (rs147785187) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with intrinsic factor deficiency … (more)
The CBLIF c.79+1G>A variant (rs147785187) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with intrinsic factor deficiency (Ferrand 2015, Overgaard 2010, Tanner 2005, Tanner 2012). This variant is reported in ClinVar (Variation ID: 439755), and is found in the general population with an overall allele frequency of 0.019% (54/282620 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 1, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Ferrand A et al. Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario. JIMD Rep. 2015;18:69-77. Overgaard UM et al. Vitamin B12 deficiency in a 15-year old boy due to mutations in the intrinsic factor gene, GIF. Br J Haematol. 2010 Aug;150(3):369-71. Tanner SM et al. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4130-3. Tanner SM et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56. (less)
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Pathogenic
(Jan 07, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary intrinsic factor deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000815651.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 1 of the GIF 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 GIF 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 GIF are known to be pathogenic (PMID: 14576042, 22929189). This variant is present in population databases (rs147785187, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with intrinsic factor deficiency (PMID: 15738392, 20408840, 22929189, 25308559). ClinVar contains an entry for this variant (Variation ID: 439755). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 15, 2005)
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no assertion criteria provided
Method: literature only
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INTRINSIC FACTOR DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021970.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 affected members of a French family with hereditary intrinsic factor deficiency (261000), Tanner et al. (2005) identified homozygosity for a G-to-A transition at … (more)
In 2 affected members of a French family with hereditary intrinsic factor deficiency (261000), Tanner et al. (2005) identified homozygosity for a G-to-A transition at +1 in the donor splice site of intron 1 of the GIF gene, predicted to lead to a loss of function. The parents were heterozygous for the mutation. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario. | Ferrand A | JIMD reports | 2015 | PMID: 25308559 |
Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. | Tanner SM | Orphanet journal of rare diseases | 2012 | PMID: 22929189 |
Vitamin B12 deficiency in a 15-year old boy due to mutations in the intrinsic factor gene, GIF. | Overgaard UM | British journal of haematology | 2010 | PMID: 20408840 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. | Tanner SM | Proceedings of the National Academy of Sciences of the United States of America | 2005 | PMID: 15738392 |
Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency. | Yassin F | Blood | 2004 | PMID: 14576042 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GIF | - | - | - | - |
Text-mined citations for rs147785187 ...
HelpRecord last updated May 27, 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.