Submissions for variant NM_025099.6(CTC1):c.833G>T (p.Gly278Val)

dbSNP: rs768853291

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000817639	SCV000958211	uncertain significance	Dyskeratosis congenita	2022-06-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 278 of the CTC1 protein (p.Gly278Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 660443). This missense change has been observed in individuals with clinical features of Coats plus syndrome (PMID: 22899577, 25843205, 29146883). This variant is present in population databases (rs768853291, gnomAD 0.007%).
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001281621	SCV001468951	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
GeneDx	RCV001281621	SCV001782916	likely pathogenic	not provided	2021-07-09	criteria provided, single submitter	clinical testing	Identified in compound heterozygous state in a patient with leukopathy, intracranial calcifications and cysts, growth retardation, and skeletal demineralization and osteopenia in published literature (Bisserbe et al., 2015); Identified by exome sequencing in two unrelated individuals in published literature (Bluteau et al., 2018) with bone marrow failure and Coats disease who each harbored a second CTC1 variant, the phase of which was unknown; Identified in patient with intracranial calcifications, microcephaly, and developmental delay in published literature (Walne et al., 2013) who harbored a second CTC1 variant, the phase of which is unknown; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22899577, 29146883, 32033110, 27535533, 25843205)
Genome-Nilou Lab	RCV001807347	SCV002054478	likely pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323734	SCV004029722	uncertain significance	not specified	2023-07-12	criteria provided, single submitter	clinical testing	Variant summary: CTC1 c.833G>T (p.Gly278Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.833G>T has been reported in the literature in bi-allelic individuals affected with Dyskeratosis congenita (Walne_2013) and Cerebro-retinal microangiopathy with calcifications and cysts (Bisserbe_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cerebroretinal Microangiopathy With Calcifications And Cysts 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25843205, 29146883, 22899577). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001807347	SCV004100756	likely pathogenic	Cerebroretinal microangiopathy with calcifications and cysts 1	2023-10-23	criteria provided, single submitter	clinical testing	Criteria applied: PM2_SUP,PP3,PS4_MOD,PM3