Submissions for variant NM_025114.4(CEP290):c.4522C>T (p.Arg1508Ter)

gnomAD frequency: 0.00002  dbSNP: rs749439750

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201597	SCV000256392	pathogenic	Joubert syndrome 5	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000521437	SCV000618464	pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 35314707, 26092869)
Eurofins Ntd Llc (ga)	RCV000521437	SCV000702711	pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036850	SCV001200236	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1508*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217639). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). This variant is present in population databases (rs749439750, gnomAD 0.003%).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000201597	SCV001367131	pathogenic	Joubert syndrome 5	2018-11-28	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
3billion, Medical Genetics	RCV002250594	SCV002521052	pathogenic	Leber congenital amaurosis 10	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000217639). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002485329	SCV002786057	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2024-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155122	SCV003844946	pathogenic	Meckel syndrome, type 4	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.4522C>T (p.Arg1508X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4522C>T has been reported in the literature in individuals affected with CEP290-related disorders, including Leber congenital amaurosis and Joubert syndrome (e.g. Rachel_2012, Bachmann-Gagescu_2015, Diderich_2021, Ginevrino_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence and demonstrated ciliation defects in fibroblasts from a patient, who carried another pathogenic variant in trans (Vandervore_2019). Eight ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003468926	SCV004216592	pathogenic	Bardet-Biedl syndrome 14	2023-07-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816349	SCV005072869	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000521437	SCV001808055	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000521437	SCV001974375	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000521437	SCV001979713	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001828040	SCV002094220	pathogenic	Leber congenital amaurosis	2020-08-07	no assertion criteria provided	clinical testing