Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000456770 | SCV000541114 | pathogenic | Dyskeratosis congenita | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys242Leufs*41) in the CTC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTC1 are known to be pathogenic (PMID: 22267198, 22387016). This variant is present in population databases (rs199473674, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with CTC1-related conditions (PMID: 22267198, 22387016, 22532422, 22899577). ClinVar contains an entry for this variant (Variation ID: 30995). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000485968 | SCV000566677 | pathogenic | not provided | 2022-08-31 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22387016, 23869908, 22532422, Riquelme2020[Poster], 31589614, 30891747, 22899577, 22267198, 34706368, 30665703) |
| Illumina Laboratory Services, |
RCV000023986 | SCV000914805 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2018-10-19 | criteria provided, single submitter | clinical testing | The CTC1 c.724_727delAAAG (p.Lys242LeufsTer41) variant has been reported in four studies and is found in a total of eight probands in a compound heterozygous state, including two probands with dyskeratosis congenita, five probands with Coats plus syndrome, and one proband with cerebroretinal microangiopathy with calcifications and cysts (Anderson et al. 2012; Keller et al. 2012; Polvi et al. 2012; Walne et al. 2013). Expression of the p.Lys242LeufsTer41 variant protein in mouse embryonic fibroblasts with the wild type copy of CTC1 knocked out, demonstrated increased telomere dysfunction and the formation of fused chromosomes (Gu et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000523 in the Latino population of the Genome Aggregation Database. Based on the available evidence and the potential impact of frameshift variants, the p.Lys242LeufsTer41 variant is classified as pathogenic for CTC1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Revvity Omics, |
RCV000023986 | SCV002019764 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2023-12-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000023986 | SCV002055623 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Genetic Services Laboratory, |
RCV000485968 | SCV002064544 | pathogenic | not provided | 2020-01-13 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the CTC1 gene demonstrated a four base pair deletion in exon 5, c.724_727del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 40 amino acids downstream of the mutation, p.Lys242Leufs*41. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CTC1 protein with potentially abnormal function. This pathogenic sequence change has previously been described in the compound heterozygous state with a second pathogenic sequence change in four different families with CTC1-related Coats plus syndrome (PMID: 22267198). |
| Fulgent Genetics, |
RCV000023986 | SCV002785788 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2022-04-14 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002513214 | SCV003618180 | pathogenic | Inborn genetic diseases | 2021-04-20 | criteria provided, single submitter | clinical testing | The c.724_727delAAAG alteration, located in exon 5 (coding exon 5) of the CTC1 gene, consists of a deletion of 4 nucleotides from position 724 to 727, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in several individuals with a variety of phenotypes including Coats plus, dyskeratosis congenita, and cerebroretinal microangiopathy with calcifications and cysts in conjunction with a second CTC1 variant (Keller, 2012; Polvi, 2012; Anderson, 2012; Walne, 2013; Shen, 2019). Based on the available evidence, this alteration is classified as pathogenic. |
| Baylor Genetics | RCV000023986 | SCV004183556 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2023-10-24 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV000485968 | SCV004226906 | pathogenic | not provided | 2022-02-04 | criteria provided, single submitter | clinical testing | PP4, PM3_very_strong, PVS1 |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000023986 | SCV004803847 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2024-01-18 | criteria provided, single submitter | clinical testing | Variant summary: CTC1 c.724_727delAAAG (p.Lys242LeufsX41) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0002 in 249584 control chromosomes. 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.724_727delAAAG has been reported in the literature in individuals affected with Cerebroretinal Microangiopathy With Calcifications And Cysts 1 (Anderson_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22267198). ClinVar contains an entry for this variant (Variation ID: 30995). Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000023986 | SCV000045277 | pathogenic | Cerebroretinal microangiopathy with calcifications and cysts 1 | 2012-08-01 | no assertion criteria provided | literature only |