Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001322176 | SCV001513033 | uncertain significance | Imerslund-Grasbeck syndrome | 2022-10-20 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 44 of the CUBN 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 CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 34979989). This variant is present in population databases (rs150901286, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1022289). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV001535839 | SCV001752444 | likely pathogenic | Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign | 2021-06-30 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV001780247 | SCV002019779 | pathogenic | not provided | 2019-09-03 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV001780247 | SCV004847368 | uncertain significance | not provided | 2023-11-13 | criteria provided, single submitter | clinical testing | The c.6821+2T>C variant in CUBN has been reported in the compound heterozygous state in 1 individual with clinical features of Imerslund-Grasbeck syndrome (proteinuria); however, they did not have megaloblastic anemia (Bedin 2020 PMID: 31613795). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1022289) and has been identified in 0.27% (112/41460) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. However, the presence of this variant may activate a cryptic splice site that is located 37 bases upstream, that if activated would lead to intron retention and may result in an additional 13 new amino acids to be translated. It is unclear how this would impact the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PVS1_Moderate, PM3. |
| Prevention |
RCV004743403 | SCV005355155 | likely pathogenic | CUBN-related disorder | 2024-06-12 | no assertion criteria provided | clinical testing | The CUBN c.6821+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is predicted to disrupt the nearby splice donor site, which may lead to aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). The c.6821+2T>C variant has been reported with a second CUBN predicted loss-of-function variant in three individuals with early childhood onset chronic isolated proteinuria with normal renal function (Bedin et al. 2020. PubMed ID: 31613795). Other predicted loss-of-function variants surrounding this region have also been reported to be associated with isolated proteinuria (Human Gene Mutation Database; Bedin et al. 2020. PubMed ID: 31613795). This variant is reported in 0.22% of alleles in individuals of African descent in gnomAD. Variants that disrupt a consensus splice donor site in CUBN are expected to be pathogenic. This variant is interpreted as likely pathogenic. |