Submissions for variant NM_025114.4(CEP290):c.2390del (p.Lys797fs)

dbSNP: rs781670422

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203973	SCV001375158	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys797Serfs*2) in the CEP290 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (PMID: 16909394, 17345604, 20690115). This variant is present in population databases (rs781670422, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with CEP290-related conditions (PMID: 29343940, 29844330). ClinVar contains an entry for this variant (Variation ID: 438223). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Pars Genome Lab	RCV001526425	SCV001736805	pathogenic	Joubert syndrome 5	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001526425	SCV001737337	pathogenic	Joubert syndrome 5	2021-06-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001536096	SCV001752806	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2024-02-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001783007	SCV002525394	pathogenic	not provided	2021-12-02	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28041643, 29343940, 21245082, 29844330)
Neuberg Centre For Genomic Medicine, NCGM	RCV001526425	SCV004047389	pathogenic	Joubert syndrome 5		criteria provided, single submitter	clinical testing	The frameshift variant c.2390del (p.Lys797SerfsTer2) in CEP290 gene has been observed in several individuals affected with CEP290-related conditions(Bryant L et.al.,2017). This variant has been reported to the ClinVar database as Pathogenic. The p.Lys797SerfsTer2 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.004931% is reported in gnomAD. This variant causes a frameshift starting with codon Lysine 797, changes this amino acid to Serine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Lys797SerfsTer2. This variant is predicted to cause loss of normal protein function. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003470638	SCV004216562	pathogenic	Bardet-Biedl syndrome 14	2024-03-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001829441	SCV004847424	pathogenic	Leber congenital amaurosis	2024-01-29	criteria provided, single submitter	clinical testing	The p.Lys797SerfsX2 variant in CEP290 has been reported in at least 2 individuals with Leber congenital amaurosis: in 1 homozygote and 1 compound heterozygote with another disease-causing variant in CEP290 (Bryant 2018 PMID: 29343940, Hosono 2018 PMID: 29844330). It has also been identified in the heterozygous state in 1 individual with retinal disease. This variant has been reported by other clinical laboratories in ClinVar (Variation ID 438223) and has been identified in 0.01% (4/41328) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This is consistent with the prevalence of the disease in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 797 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the CEP290 gene is an established disease mechanism in autosomal recessive CEP290-related ciliopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CEP290-related ciliopathy. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504815	SCV000599190	uncertain significance	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001783007	SCV002037489	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001783007	SCV002038424	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001829441	SCV002094289	pathogenic	Leber congenital amaurosis	2020-03-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535629	SCV004718510	pathogenic	CEP290-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The CEP290 c.2390delA variant is predicted to result in a frameshift and premature protein termination (p.Lys797Serfs*2). This variant has been reported in homozygous and compound heterozygous states in patients with Leber congenital amaurosis (LCA) and other retinal degeneration disorders (Bryant et al. 2018. PubMed ID: 29343940; Hosono et al. 2018. PubMed ID: 29844330). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.