Submissions for variant NM_005142.3(CBLIF):c.290T>C (p.Met97Thr)

gnomAD frequency: 0.00842  dbSNP: rs150884181

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000329880	SCV000372575	benign	Hereditary intrinsic factor deficiency	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000329880	SCV001107000	benign	Hereditary intrinsic factor deficiency	2025-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000329880	SCV003800377	uncertain significance	Hereditary intrinsic factor deficiency	2024-11-21	criteria provided, single submitter	clinical testing	The CBLIF c.290T>C p.Met97Thr variant (rs150884181, ClinVar Variation ID: 305040) has been observed in trans opposite the pathogenic c.79+1G>A variant in two individuals recruited for suspicion of inherited VB12 deficiency (Overgaard 2010 and Tanner 2012). Additionally, individuals heterozygous for the p.Met97Thr variant and harboring the FUT2 polymorphic “secretor” genotype (rs601338 GG/GA) have been shown to have an increased risk for VB12 deficiency (Chery 2013) and neural tube defects (NTDs; Gueant-Rodriguez 2018). Functional studies have also shown that CBLIF protein harboring the p.Met97Thr variant has a reduced ability to bind VB12 (Chery 2013). However, the p.Met97Thr variant is common in the general population and is specifically found in the Finnish population with an allele frequency of 3.6% (909/25108 alleles, including 24 homozygotes) in the Genome Aggregation Database. This suggests that the p.Met97Thr variant may be a contributing risk factor in elevated VB12, but is unlikely to have a strong, monogenic effect. Due to conflicting information, the clinical significance of the p.Met97Thr variant is uncertain at this time. References: Gueant-Rodriguez RM et al. Association of combined GIF290T>C heterozygous mutation/FUT2 secretor variant with neural tube defects. Clin Genet. 2018 Jan;93(1):191-193. PMID: 28742214. Chery C, et al. Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie. 2013 May;95(5):995-100. PMID: 23402911. 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. PMID: 20408840 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. PMID: 22929189
CeGaT Center for Human Genetics Tuebingen	RCV003114474	SCV004698376	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CBLIF: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV003114474	SCV005324350	benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003920258	SCV004733766	likely benign	CBLIF-related disorder	2020-04-29	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).