Submissions for variant NM_025099.6(CTC1):c.2012C>G (p.Ser671Cys)

gnomAD frequency: 0.00003  dbSNP: rs764799661

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001122623	SCV001281360	uncertain significance	Dyskeratosis congenita	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002070002	SCV002496087	uncertain significance	Cerebroretinal microangiopathy with calcifications and cysts 1	2022-01-28	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in 0.006% (4/68032) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-8232409-G-C?dataset=gnomad_r3). It is also present in ClinVar (Variation ID:888978). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Invitae	RCV001122623	SCV003279441	uncertain significance	Dyskeratosis congenita	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 671 of the CTC1 protein (p.Ser671Cys). This variant is present in population databases (rs764799661, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CTC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 888978). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.