rs199473677

Positions:

• chr17-8230395-AG-A
• chr17-8230395-AG-AGG

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.2831del​(p.Pro944LeufsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,614,126 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 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CTC1 NM_025099.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.393

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 17-8230395-AG-A is Pathogenic according to our data. Variant chr17-8230395-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 31000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-8230395-AG-A is described in Lovd as [Pathogenic]. Variant chr17-8230395-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTC1	NM_025099.6	c.2831del	p.Pro944LeufsTer7	frameshift_variant	17/23	ENST00000651323.1	NP_079375.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTC1	ENST00000651323.1	c.2831del	p.Pro944LeufsTer7	frameshift_variant	17/23		NM_025099.6	ENSP00000498499	P1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00368

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000409 AC: 102 AN: 249486 Hom.: 0 AF XY: 0.000369 AC XY: 50 AN XY: 135350

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000196 AC: 287 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.000186 AC XY: 135 AN XY: 727240

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74438

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000953 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebroretinal microangiopathy with calcifications and cysts 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2023	Variant summary: CTC1 c.2831delC (p.Pro944LeufsX7) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00041 in 249486 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in CTC1 causing Cerebroretinal Microangiopathy With Calcifications And Cysts 1 (0.00041 vs 0.0011), allowing no conclusion about variant significance. c.2831delC has been reported in trans along with second disease-causing variants in multiple individuals affected with Cerebroretinal Microangiopathy With Calcifications And Cysts 1 (example: Polvi_2012). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 22387016). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (all pathogenic). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	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: protein truncation and anomalous telomere replication (Gu 2013); This variant is associated with the following publications: (PMID: 23869908, 31028847, 22387016, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 30, 2020	DNA sequence analysis of the CTC1 gene demonstrated a 1 base pair deletion in exon 17, c.2831del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 7 amino acids downstream of the mutation, p.Pro944Leufs*7. 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 sequence change has been described in the gnomAD database with a frequency of 0.28% in the Finnish sub-population (dbSNP rs779650334). The p.Pro944Leufs*7 change has been reported in several unrelated Finnish individuals with cerebroretinal microangiopathy with calcifications and cysts (PMID: 22387016). Other frameshift deletions have been reported downstream of this sequence change in individuals with cerebroretinal microangiopathy with calcifications and cysts and paroxysmal nocturnal haemoglobinuria (PMIDs: 22387016, 30891747). Functional studies have demonstrated loss of protein function in the presence of a truncating variant in the homologous residue in mice (p.Pro939*) (PMID: 23869908).These collective evidences indicate that this is a pathogenic sequence change. -

Coats plus syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 14, 2018

The p.Pro944fs variant in CTC1 has been reported in the compound heterozygous st ate in at least 5 individuals with cerebroretinal microangiopathy with calcifica tions and cysts (CRMCC, also known as Coats plus syndrome; Polvi 2012). It has a lso been identified in 0.3% (73/25790) of Finnish chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473677). This variant is predicted to cause a frameshift, which alters the protein?s amin o acid sequence beginning at position 944 and leads to a premature termination c odon 7 amino acids downstream. This alteration is then predicted to lead to a tr uncated or absent protein. In vitro functional studies support that this variant impacts protein function (Gu 2013). Multiple loss of function variants in the C TC1 gene have been reported in individuals with CRMCC; however, to date, there a re no individuals with 2 null variants, suggesting that biallelic loss-of-functi on mutations might be incompatible with life (Anderson 2012; Polvi 2012). In sum mary, this variant is pathogenic. ACMG/AMP Criteria applied: PVS1; PP4; PM3_Supp orting. -

CTC1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

The CTC1 c.2831delC variant is predicted to result in a frameshift and premature protein termination (p.Pro944Leufs*7). This variant has been reported as pathogenic for autosomal recessive cerebroretinal microangiopathy with calcifications and cysts (Polvi et al. 2012. PubMed ID: 22387016). This variant is reported in 0.28% 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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change creates a premature translational stop signal (p.Pro944Leufs*7) 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 (rs199473677, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. 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: 31000). 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)		0.0		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

Other links and lift over

dbSNP: rs199473677; hg19: chr17-8133713;