ClinVar Miner

Submissions for variant NM_025099.6(CTC1):c.2923A>G (p.Arg975Gly) (rs199473678)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778131 SCV000914256 likely pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2019-04-05 criteria provided, single submitter clinical testing The CTC1 c.2923A>G (p.Arg975Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state with a null variant in two individuals with cerebroretinal microangiopathy with calcifications and cysts (CRMCC or Coats Plus syndrome) (Anderson et al. 2012; Polvi et al. 2012). The p.Arg975Gly variant was absent from 2,097 control subjects but is reported at a frequency of 0.000154 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrate that the p.Arg975Gly variant was found to reduce telomere association in vivo to 83% that of wild type, while other telomeric functions were found to be preserved, similar to those of wild type (Chen et al. 2013). Wang et al. (2018) showed that unlike wild type CTC1, the p.Arg975Gly variant failed to completely restore the chromosome abnormalities, RAD51 foci formation, and proliferation defects caused by CTC1 knockdown in cells and that the p.Arg975Gly variant significantly reduced CTC1 association to genomic fragile sites in response to replication stress indicating that this residue might be critical for RAD51 binding. Based on the evidence, the p.Arg975Gly variant is classified as likely pathogenic for CTC1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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