ClinVar Miner

Submissions for variant NM_025099.6(CTC1):c.724_727del (p.Lys242fs) (rs199473674)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456770 SCV000541114 pathogenic Dyskeratosis congenita 2020-01-07 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 5 of the CTC1 mRNA (c.724_727delAAAG), causing a frameshift at codon 242. This creates a premature translational stop signal (p.Lys242Leufs*41) and is expected to result in an absent or disrupted protein product. Truncating variants in CTC1 are known to be pathogenic. This particular truncation has been reported in the literature in individuals affected with Coats plus, dyskeratosis congenita, and cerebroretinal microangiopathy with calcifications and cysts. In each case, this variant was reported in compound heterozygosity with a non-truncating CTC1 variant (PMID: 22267198, 22532422, 22387016, 22899577). Experimental studies using CTC1 null mouse embryonic fibroblasts have shown that this variant produces truncated or unstable CTC1 protein, is not capable of forming a CST complex required for telomere replication, and represses the expression of the CTC1 missense allele (PMID: 23869908). In addition, patient-derived blood samples carrying this variant were shown to have shortened telomeres (PMID: 22267198, 22532422). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000485968 SCV000566677 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing The c.724_727delAAAG variant in the CTC1 gene has been reported previously in individuals with CRMCC who are also heterozygous for additional variants in the CTC1 gene (Anderson et al., 2012; Polvi et al., 2012). The c.724_727delAAAG variant causes a frameshift starting with codon Lysine 242, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 41 of the new reading frame, denoted p.Lys242LeufsX41. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.724_727delAAAG variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.724_727delAAAG as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina 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.
OMIM RCV000023986 SCV000045277 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2012-08-01 no assertion criteria provided literature only

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