Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000001816 | SCV000831797 | likely pathogenic | Hereditary intrinsic factor deficiency | 2024-08-13 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 46 of the GIF protein (p.Ser46Leu). This variant is present in population databases (rs121434322, gnomAD 0.1%). This missense change has been observed in individual(s) with intrinsic factor deficiency (PMID: 22929189). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GIF protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000001816 | SCV000967619 | likely pathogenic | Hereditary intrinsic factor deficiency | 2023-07-26 | criteria provided, single submitter | clinical testing | The p.Ser46Leu variant in CBLIF (previously known as GIF) has been reported in 1 compound heterozygous and 2 homozygous individuals with congenital intrinsic factor deficiency and segregated with disease in 3 affected relatives from 1 family (Tanner 2005 PMID: 15738392, Tanner 2012 PMID: 22929189). The p.Ser46Leu variant has been identified in 0.01% (2/15272) of Latino/Admixed (as well as other populations) chromosomes by gnomAD, v3.1.2 (http://gnomad.broadinstitute.org). It has also been reported in ClinVar (Variation ID 1746). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Ser46Leu variant is likely pathogenic for autosomal recessive congenital intrinsic factor deficiency. ACMG/AMP Criteria applied: PM3_strong, PP1_Moderate, PM2_Supporting. |
| OMIM | RCV000001816 | SCV000021972 | pathogenic | Hereditary intrinsic factor deficiency | 2005-03-15 | no assertion criteria provided | literature only |