rs199473674

Positions:

chr17-8237439-GCTTT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_025099.6(CTC1):c.724_727del(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.20

Variant links:

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]

CTC1 links:

Genome browser will be placed here

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

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6 linkuse as main transcript	c.724_727del	p.Lys242LeufsTer41	frameshift_variant	5/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1 linkuse as main transcript	c.724_727del	p.Lys242LeufsTer41	frameshift_variant	5/23		NM_025099.6	P1	Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

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:

AN:

249584

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135408

show subpopulations

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.:

AF XY:

0.000259

AC XY:

188

AN XY:

727058

show subpopulations

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:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74240

show subpopulations

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.:

Bravo

AF:

0.000321

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2012	- -
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	Genome-Nilou Lab	Jul 15, 2021	- -
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	Revvity Omics, Revvity	Dec 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 14, 2022	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 04, 2022	PP4, PM3_very_strong, PVS1 -
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). -

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. -

Dyskeratosis congenita

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over