rs199473679

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM4_SupportingPP5_Very_Strong

The NM_025099.6(CTC1):c.2954_2956delGTT(p.Cys985del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000192 in 1,614,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CTC1
NM_025099.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.46

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

cerebroretinal microangiopathy with calcifications and cysts 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
dyskeratosis congenita
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
Coats plus syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CTC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_025099.6. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 17-8229945-AAAC-A is Pathogenic according to our data. Variant chr17-8229945-AAAC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 40250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.2954_2956delGTT	p.Cys985del	disruptive_inframe_deletion	Exon 18 of 23	ENST00000651323.1	NP_079375.3	Q2NKJ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1 link	c.2954_2956delGTT	p.Cys985del	disruptive_inframe_deletion	Exon 18 of 23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

249534

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461878

Hom.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000131

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41558

American (AMR)

AF:

0.00105

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000317

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:3

Dec 24, 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.2954_2956delGTT (p.Cys985del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 249534 control chromosomes. c.2954_2956delGTT has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with bone marrow failure, myelodysplastic syndrome, and dyskeratosis congenita (Bluetau_2018, Guiduglii_2017, Walne_2013, Keller_pediatr). These data indicate that the variant is likely to be associated with disease. Experimental studies report that this variant impacts telomere stability (Gu_2013, Chen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 29146883, 24115768, 23869908, 28104920, 22532422, 22899577). ClinVar contains an entry for this variant (Variation ID: 40250). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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.2954_2956del; p.Cys985del variant (rs199473679) is reported in the literature in individuals affected with bone marrow failure syndromes as a homozygous variant or as a heterozygous variant in individuals who also carry a pathogenic variant in trans (Guidugli 2017, Keller 2012, Polvi 2012, Shen 2019, Walne 2013). This variant is also reported in ClinVar (Variation ID: 40250). This variant is found in the general population with an overall allele frequency of 0.002% (5/249,534 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show reduced telomere length (Anderson 2012, Gu 2013, Keller 2012). This variant deletes a single cysteine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be pathogenic. References: Anderson BH et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nature genetics. 2012 Mar. PMID: 22267198. Gu P et al. Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. Aging Cell. 2013 Dec. PMID: 23869908. Guidugli L et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017 Feb 07. PMID: 28104920. 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. -

not provided

Pathogenic:2

Feb 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3_strong, PM4, PS3, PS4_moderate -

Dec 18, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate p.C985del damages normal protein function and affects genome instability (Wang et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 25197929, 22899577, 33010065, 24115768, 32499435, 23869908, 22387016, 22532422, 29146883, 30891747, 30523342, 33034244, 32543263, 28104920, 29481669, 22267198) -

Dyskeratosis congenita

Pathogenic:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2954_2956del, results in the deletion of 1 amino acid(s) of the CTC1 protein (p.Cys985del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs199473679, gnomAD 0.009%). This variant has been observed in individuals with Coats plus, dyskeratosis congenita, and cerebroretinal microangiopathy with calcifications and cysts (PMID: 22267198, 22387016, 22532422, 22899577). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CTC1 function (PMID: 22267198, 22532422, 23869908, 24115768). For these reasons, this variant has been classified as Pathogenic. -

Oct 10, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CTC1 c.2954_2956del (p.Cys985del) change deletes three nucleotides resulting in an in-frame deletion of one amino acid at codon 985 in exon 18. This change has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant was shown to impair telomere maintenance, leading to significantly shortened telomeres and increased yH2AX-positive cells, indicating elevated DNA damage and genomic instability. Cellular assays demonstrated defects in fibroblast proliferation, increased senescence, and a higher frequency of chromosome fusions. This variant also disrupted the formation of the CST complex, reducing its ability to bind single-stranded telomeric DNA and localize to telomeres. (PMID: 22267198, 22532422, 23869908). This variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals affected with dyskeratosis congenita Coats plus syndrome. (PMID: 22267198, 30891747, 32543263, 35580952, 37974921). In summary, this variant meets criteria to be classified as pathogenic. -

Coats plus syndrome

Pathogenic:1

Jul 30, 2018

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.5

Mutation Taster

=44/56

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over