rs199473674

Variant names:

• chr17-8237439-GCTTT-G
• rs199473674
• NM_025099.6:c.724_727delAAAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• 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]

ACMG classification

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6	c.724_727delAAAG	p.Lys242LeufsTer41	frameshift_variant	Exon 5 of 23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.724_727delAAAG	p.Lys242LeufsTer41	frameshift_variant	Exon 5 of 23		NM_025099.6	ENSP00000498499.1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151992 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 249584 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1461468 Hom.: 0 AF XY: 0.000259 AC XY: 188 AN XY: 727058

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151992 Hom.: 0 Cov.: 29 AF XY: 0.000175 AC XY: 13 AN XY: 74240

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1 Pathogenic:8

Oct 19, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jan 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 18, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jan 13, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Feb 04, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM3_very_strong, PVS1 -

Aug 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Inborn genetic diseases Pathogenic:1

Apr 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

CTC1-related disorder Pathogenic:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473674; hg19: chr17-8140757;