rs199473674
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_025099.6(CTC1):c.724_727delAAAG(p.Lys242LeufsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 29)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
CTC1
NM_025099.6 frameshift
NM_025099.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.20
Genes affected
CTC1 (HGNC:26169): (CST telomere replication complex component 1) This gene encodes a component of the CST complex. This complex plays an essential role in protecting telomeres from degradation. This protein also forms a heterodimer with the CST complex subunit STN1 to form the enzyme alpha accessory factor. This enzyme regulates DNA replication. Mutations in this gene are the cause of cerebroretinal microangiopathy with calcifications and cysts. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-8237439-GCTTT-G is Pathogenic according to our data. Variant chr17-8237439-GCTTT-G is described in ClinVar as [Pathogenic]. Clinvar id is 30995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8237439-GCTTT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.000178 AC: 27AN: 151992Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.000200 AC: 50AN: 249584Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135408
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GnomAD4 exome AF: 0.000288 AC: 421AN: 1461468Hom.: 0 AF XY: 0.000259 AC XY: 188AN XY: 727058
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GnomAD4 genome 0.000178 AC: 27AN: 151992Hom.: 0 Cov.: 29 AF XY: 0.000175 AC XY: 13AN XY: 74240
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cerebroretinal microangiopathy with calcifications and cysts 1 Pathogenic:8
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 18, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 05, 2024 | The CTC1 c.724_727del; p.Lys242LeufsTer41variant (rs199473674) is reported in the literature in individuals affected with bone marrow failure syndromes who also carry a pathogenic variant in trans (Keller 2012, Polvi 2012, Shen 2019, Walne 2013). This variant is also reported in ClinVar (Variation ID: 30995). This variant is found in the general population with an overall allele frequency of 0.02% (54/280,872 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Keller RB et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatric blood & cancer. 2012 Aug. PMID: 22532422. Polvi A et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet. 2012 Mar 9. PMID: 22387016. Shen W et al. Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure. Br J Haematol. 2019 Jun. PMID: 30891747. Walne AJ et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica. 2013 Mar. PMID: 22899577. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 19, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 18, 2023 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 31, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 13, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 04, 2022 | PP4, PM3_very_strong, PVS1 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2021 | 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. - |
CTC1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2024 | The CTC1 c.724_727delAAAG variant is predicted to result in a frameshift and premature protein termination (p.Lys242Leufs*41). This variant has been reported to be causative for autosomal recessive cerebroretinal microangiopathy with calcifications and cysts, which is also known as Coats plus (Polvi et al. 2012. PubMed ID: 22387016; Anderson et al. 2012. PubMed ID: 22267198). This variant is reported in 0.054% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in CTC1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Dyskeratosis congenita Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2025 | 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at