Submissions for variant NM_005142.3(CBLIF):c.79+1G>A

gnomAD frequency: 0.00017  dbSNP: rs147785187

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000734690	SCV000603809	pathogenic	not provided	2020-02-16	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000688054	SCV000815651	pathogenic	Hereditary intrinsic factor deficiency	2024-01-07	criteria provided, single submitter	clinical testing	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.
Eurofins Ntd Llc (ga)	RCV000734690	SCV000862849	pathogenic	not provided	2018-08-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000688054	SCV000915532	pathogenic	Hereditary intrinsic factor deficiency	2018-10-16	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000688054	SCV000966891	pathogenic	Hereditary intrinsic factor deficiency	2018-12-05	criteria provided, single submitter	clinical testing	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.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000688054	SCV001149783	pathogenic	Hereditary intrinsic factor deficiency	2020-01-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197357	SCV001368065	pathogenic	See cases	2019-06-03	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2,PM3.
OMIM	RCV000688054	SCV000021970	pathogenic	Hereditary intrinsic factor deficiency	2005-03-15	no assertion criteria provided	literature only