Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000023993 | SCV003844293 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2024-06-11 | criteria provided, single submitter | clinical testing | Variant summary: CTC1 c.1994T>G (p.Val665Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249480 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CTC1 causing cerebroretinal microangiopathy with calcifications and cysts 1 (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.1994T>G has been reported in the literature in multiple individuals affected with cerebroretinal microangiopathy with calcifications (CRMCC), including cases where it has been confirmed to be in trans with a pathogenic variant and in families where it has segregated with the disease phenotype (e.g. Polvi_2012, Mansukhani_2017, Feurstein_2021). These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence suggesting that the variant has an impact on protein function, reducing telomere association and impairing response to replication stress (e.g. Chen_2013, Wang_2018). The following publications have been ascertained in the context of this evaluation (PMID: 24115768, 28864049, 22387016, 29481669, 33510405). ClinVar contains an entry for this variant (Variation ID: 31002). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV003227608 | SCV003924725 | pathogenic | not provided | 2023-05-08 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with impaired telomere replication, global genome instabilities, and decreased cell proliferation and survival (Gu et al., 2013; Chen et al., 2013, Wang et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23869908, 24115768, 22387016, 29481669, 33510405, 33780718) |
| Fulgent Genetics, |
RCV000023993 | SCV005652898 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2024-06-20 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV005089310 | SCV005773627 | pathogenic | Dyskeratosis congenita | 2024-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 665 of the CTC1 protein (p.Val665Gly). This variant is present in population databases (rs199473676, gnomAD 0.2%). This missense change has been observed in individual(s) with cerebroretinal microangiopathy with calfications and cysts (PMID: 22387016). 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: 31002). Invitae Evidence 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 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 CTC1 protein function. Experimental studies have shown that this missense change affects CTC1 function (PMID: 2411576, 23869908, 29481669). For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000023993 | SCV000045284 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2012-03-09 | no assertion criteria provided | literature only |