dbSNP rs199473680: CTC1:p.Leu1007CysfsTer62 (chr17-8229438-AG-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_025099.6(CTC1):c.3019delC(p.Leu1007CysfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,613,124 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CTC1
NM_025099.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.525

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 17-8229438-AG-A is Pathogenic according to our data. Variant chr17-8229438-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 843472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8229438-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTC1	NM_025099.6 link	c.3019delC	p.Leu1007CysfsTer62	frameshift_variant	Exon 19 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.3019delC	p.Leu1007CysfsTer62	frameshift_variant	Exon 19 of 23		NM_025099.6	ENSP00000498499.1		Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000189

AC:

AN:

248864

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.000186

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000166

AC:

243

AN:

1460886

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

726838

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.000170

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000112

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000869

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:4

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM2_SUP,PS3_SUP,PM3 -

not provided

Pathogenic:3

Sep 08, 2023

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; Published functional studies demonstrate a damaging effect: anomalous telomere replication (Gu et al., 2013); This variant is associated with the following publications: (PMID: 22387016, 23869908, 34308104) -

Nov 28, 2022

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the CTC1 gene demonstrated a single base pair deletion in exon 19, c.3019del. This sequence change results in an amino acid frameshift and creates a premature stop codon 61 amino acids downstream of the change, p.Leu1007Cysfs*62. This 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 sequence change has been described in the gnomAD database with a frequency of 0.11% in the Finnish subpopulation and 0.019% in the overall population (dbSNP rs199473680). This pathogenic sequence change has previously been described in the compound heterozygous state in an individual with cerebroretinal microangiopathy with calcifications and cysts (PMID: 22387016). A functional study in mouse cDNA indicates that this sequence change causes loss-of-function (PMID: 23869908). These collective evidences indicate that this sequence change is pathogenic. This pathogenic sequence change in the heterozygous state is not sufficient to cause this individual’s phenotype. -

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Coats plus syndrome

Pathogenic:1

Apr 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu1007CysfsX62 variant in CTC1 has been reported in 1 compound heterozygous, Finnish individual with clinical features of cerebroretinal microangiopathy with calcifications and cysts-1 (CRMCC1) (Polvi 2012). This variant has also been identified in 0.02% (13/66568) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473680). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1007 and leads to a premature termination codon 62 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vitro and mouse model functional studies also provide evidence that the p.Leu1007CysfsX62 variant impacts protein function (Gu 2013). No individuals affected with CRMCC1 reported to date are compound heterozygous or homozygous for 2 null variants, suggesting that biallelic null mutations might be incompatible with development (Anderson 2012). In summary, this variant meets criteria to be classified as pathogenic for CRMCC1 in an autosomal recessive manner based upon case observation, functional evidence and low frequency in controls. -

CTC1-related disorder

Pathogenic:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CTC1 c.3019delC variant is predicted to result in a frameshift and premature protein termination (p.Leu1007Cysfs*62). This variant has been reported in the compound heterozygous state in an individual with cerebroretinal microangiopathy with calcifications and cysts (CRMCC), while the patient’s heterozygous father was unaffected (Polvi et al. 2012. PubMed ID: 22387016). Functional studies of mouse CTC1 p.L1002*, which is the equivalent to human CTC1 p.Leu1007Cysfs*62, showed that the variant lead to a disruption of CST complex formation, which is necessary for telomere replication (Gu et al. 2013. PubMed ID: 23869908). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in CTC1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Dyskeratosis congenita

Pathogenic:1

Feb 03, 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.Leu1007Cysfs*62) 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 (rs199473680, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with cerebroretinal microangiopathy with calcifications and cysts (PMID: 22387016). ClinVar contains an entry for this variant (Variation ID: 843472). 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)

0.0

Details are displayed if max score is > 0.2

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

Publications

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