ClinVar Genomic variation as it relates to human health
NM_025099.6(CTC1):c.724_727del (p.Lys242fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_025099.6(CTC1):c.724_727del (p.Lys242fs)
Variation ID: 30995 Accession: VCV000030995.28
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17p13.1 17: 8237440-8237443 (GRCh38) [ NCBI UCSC ] 17: 8140758-8140761 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 13, 2017 May 1, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_025099.6:c.724_727del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079375.3:p.Lys242fs frameshift NM_025099.6:c.724_727delAAAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000017.11:g.8237442_8237445del NC_000017.10:g.8140760_8140763del NG_032148.2:g.15653_15656del LRG_1124:g.15653_15656del LRG_1124t1:c.724_727del LRG_1124p1:p.Lys242fs - Protein change
- K242fs
- Other names
- p.Lys242Leufs*41
- Canonical SPDI
- NC_000017.11:8237439:CTTTCT:CT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CTC1 | - | - |
GRCh38 GRCh37 |
1356 | 1471 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000023986.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 31, 2022 | RCV000485968.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000456770.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2021 | RCV002513214.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914805.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002055623.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Jan 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064544.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004183556.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226906.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM3_very_strong, PVS1
Number of individuals with the variant: 1
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Pathogenic
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019764.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Dyskeratosis congenita
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000541114.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803847.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cerebroretinal microangiopathy with calcifications and cysts 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002785788.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000566677.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Apr 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003618180.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Aug 01, 2012)
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no assertion criteria provided
Method: literature only
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CEREBRORETINAL MICROANGIOPATHY WITH CALCIFICATIONS AND CYSTS 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045277.4
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2017 |
Comment on evidence:
In 2 Scottish sisters and an unrelated English patient, all with Coats plus syndrome (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 … (more)
In 2 Scottish sisters and an unrelated English patient, all with Coats plus syndrome (CRMCC1; 612199), Anderson et al. (2012) identified compound heterozygosity for 2 mutations in the CTC1 gene: a 4-bp deletion (724_727delAAAG) in exon 5, resulting in a frameshift and premature termination, and a 2959C-T transition in exon 18, resulting in an arg987-to-trp (R987W; 613129.0002) substitution. The missense mutation affected a residue well-conserved among mammals, and neither mutation was found in 1,730 controls. The patients had previously been reported by Briggs et al. (2008). All had intrauterine growth retardation, intracranial calcifications, leukoencephalopathy, early-onset retinal changes, and gastrointestinal ectasia. The sisters both had gray hair, translucent skin, and dystrophic nails, and the English patient had anemia. One of the sisters and the English patient had early-onset bone fractures. The 2 sisters died in their early twenties of gastrointestinal bleeding. One of the patients was found to have shortened telomere lengths in white blood cells, and each heterozygous parent had telomere lengths at the lower range of normal. Keller et al. (2012) reported an 18-year-old girl who was compound heterozygous for 724_727delAAAG and a 3-bp deletion (c.2954_2956delGTT; 613129.0012) in the CTC1 gene. The patient presented at age 15 years with classic features of dyskeratosis congenita (see, e.g., 127550), including bone marrow failure, abnormalities in skin pigmentation, nail dysplasia, and graying hair. She also had short stature, osteopenia, decreased pulmonary function, and blurry vision associated with sheathed vessels and microaneurysm formation in the retina. Brain MRI showed calcifications in the right thalamus, and telomeres were shortened significantly. Neurologic function was normal. Patient fibroblasts showed a defect in outgrowth as well as rapid senescence compared to controls. Keller et al. (2012) noted that both CTC1 mutations had been reported in patients with Coats plus syndrome, suggesting that Coats plus syndrome and DKC show phenotypic and genetic overlap, consistent with a telomere-related disease. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1. | Riquelme J | Hormone research in paediatrics | 2021 | PMID: 34706368 |
Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure. | Shen W | British journal of haematology | 2019 | PMID: 30891747 |
Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. | Gu P | Aging cell | 2013 | PMID: 23869908 |
Mutations in the telomere capping complex in bone marrow failure and related syndromes. | Walne AJ | Haematologica | 2013 | PMID: 22899577 |
CTC1 Mutations in a patient with dyskeratosis congenita. | Keller RB | Pediatric blood & cancer | 2012 | PMID: 22532422 |
Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. | Polvi A | American journal of human genetics | 2012 | PMID: 22387016 |
Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. | Anderson BH | Nature genetics | 2012 | PMID: 22267198 |
Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). | Briggs TA | American journal of medical genetics. Part A | 2008 | PMID: 18076099 |
Text-mined citations for rs199473674 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.