Submissions for variant NM_025099.6(CTC1):c.3247G>A (p.Glu1083Lys)

gnomAD frequency: 0.00009  dbSNP: rs201885165

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001051224	SCV000407593	uncertain significance	Dyskeratosis congenita	2018-01-13	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051224	SCV001215368	uncertain significance	Dyskeratosis congenita	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1083 of the CTC1 protein (p.Glu1083Lys). This variant is present in population databases (rs201885165, gnomAD 0.03%). 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: 326066). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CTC1 protein function with a positive predictive value of 80%. 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.
Genome-Nilou Lab	RCV001807216	SCV002055583	uncertain significance	Cerebroretinal microangiopathy with calcifications and cysts 1	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021722	SCV004850983	uncertain significance	Inborn genetic diseases	2024-03-11	criteria provided, single submitter	clinical testing	The c.3247G>A (p.E1083K) alteration is located in exon 21 (coding exon 21) of the CTC1 gene. This alteration results from a G to A substitution at nucleotide position 3247, causing the glutamic acid (E) at amino acid position 1083 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726117	SCV001963521	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726117	SCV001970526	uncertain significance	not provided		no assertion criteria provided	clinical testing