Submissions for variant NM_025099.6(CTC1):c.3019del (p.Leu1007fs)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001046110	SCV001209998	pathogenic	Dyskeratosis congenita	2023-12-13	criteria provided, single submitter	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.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001281622	SCV001468952	pathogenic	not provided		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784596	SCV002019762	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2019-09-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001784596	SCV002055619	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001281622	SCV004034403	pathogenic	not provided	2023-09-08	criteria provided, single submitter	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)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001784596	SCV004100754	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2023-10-23	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM2_SUP,PS3_SUP,PM3
PreventionGenetics, part of Exact Sciences	RCV003963008	SCV004780809	pathogenic	CTC1-related condition	2024-02-07	criteria provided, single submitter	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.
Genetic Services Laboratory, University of Chicago	RCV001281622	SCV003839403	pathogenic	not provided	2022-11-28	no assertion criteria provided	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.