ClinVar Miner

Submissions for variant NM_025099.6(CTC1):c.2831del (p.Pro944fs) (rs199473677)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233824 SCV000290908 pathogenic Dyskeratosis congenita 2019-10-06 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 17 of the CTC1 mRNA (c.2831delC), causing a frameshift at codon 944. This creates a premature translational stop signal (p.Pro944Leufs*7) and is expected to result in an absent or disrupted protein product. Truncating variants in CTC1 are known to be pathogenic. This particular truncation has been reported in several individuals from unrelated families affected with cerebroretinal microangiopathy with calcifications and cysts (PMID: 22387016). ClinVar contains an entry for this variant (Variation ID: 31000). This variant is present in the Finnish population of the ExAC database with an allele frequency of 0.4% (rs199473677). This, in conjunction with the observation of this variant in multiple affected Finnish families (PMID: 22387016), may indicate that this variant is a founder mutation in this population. Experimental studies have shown that a truncation of the protein at the homologous residue in mouse CTC1 (p.Pro939*) resulted in a truncated product and loss of protein function (PMID: 23869908). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255650 SCV000322382 pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing The c.2831delC pathogenic variant in the CTC1 gene has been reported previously in combination with another CTC1 variant in multiple individuals with cerebroretinal microangiopathy with calcifications and cysts (CRMCC) (Polvi et al., 2012). The c.2831delC variant causes a frameshift starting with codon Proline 944, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Pro944LeufsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies confirm that c.2831delC leads to protein truncation as well as anomalous telomere replication (Gu and Chang, 2013). The c.2831delC variant is observed in 73/25,790 (0.28%) alleles from individuals of Finnish background and 131/277,100 (0.047%) total alleles in large population cohorts (Lek et al., 2016). We interpret c.2831delC as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825561 SCV000966887 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 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,; 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.
OMIM RCV000023991 SCV000045282 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2012-03-09 no assertion criteria provided literature only

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