Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001051564 | SCV001215725 | likely pathogenic | Dyskeratosis congenita | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 840 of the CTC1 protein (p.Arg840Trp). This variant is present in population databases (rs373905859, gnomAD 0.007%). This missense change has been observed in individual(s) with cerebroretinal microangiopathy with calcifications and cysts type 1 (PMID: 22267198). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30999). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CTC1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CTC1 function (PMID: 23869908, 24115768, 29228254, 29481669). 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. |
| Gene |
RCV001551084 | SCV001771511 | likely pathogenic | not provided | 2021-01-07 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect of genome instability (Wang et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in siblings with Coats plus syndrome who harbored a missense variant on the opposite allele (in trans) (Anderson et al., 2012); This variant is associated with the following publications: (PMID: 22267198, 27239262, 29481669, 29228254, 24115768, 23869908) |
| Genome- |
RCV000023990 | SCV002055630 | uncertain significance | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000023990 | SCV000045281 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2012-01-22 | no assertion criteria provided | literature only |