Submissions for variant NM_025099.6(CTC1):c.2831del (p.Pro944fs)

dbSNP: rs199473677

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233824	SCV000290908	pathogenic	Dyskeratosis congenita	2023-12-01	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000255650	SCV000322382	pathogenic	not provided	2020-12-21	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: protein truncation and anomalous telomere replication (Gu 2013); This variant is associated with the following publications: (PMID: 23869908, 31028847, 22387016, 31589614)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825561	SCV000966887	pathogenic	Coats plus syndrome	2018-05-14	criteria provided, single submitter	clinical testing	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.
Genome-Nilou Lab	RCV000023991	SCV002055621	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255650	SCV002067457	pathogenic	not provided	2020-03-30	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023991	SCV004029721	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2023-07-12	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000023991	SCV000045282	pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2012-03-09	no assertion criteria provided	literature only