Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000001816 | SCV000831797 | likely pathogenic | Hereditary intrinsic factor deficiency | 2024-01-07 | 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 | 2018-11-06 | criteria provided, single submitter | clinical testing | The p.Ser46Leu variant in GIF has been reported in 1 compound heterozygous and 2 homozygous individuals with congenital intrinsic factor deficiency and segregat ed with disease in 3 affected relatives from 1 family (Tanner 2005, Tanner 2012) . The p.Ser46Leu variant has been identified in 0.1% (34/35436) of Latino chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg). Computational prediction tools and conservation analysis suggest that the p .Ser46Leu variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, although additional studies a re required to fully establish its clinical significance, the p.Ser46Leu variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PP1, PM2_Supportin g, PP3. |
| OMIM | RCV000001816 | SCV000021972 | pathogenic | Hereditary intrinsic factor deficiency | 2005-03-15 | no assertion criteria provided | literature only |