Submissions for variant NM_025114.4(CEP290):c.4393C>T (p.Arg1465Ter)

gnomAD frequency: 0.00002  dbSNP: rs539400286

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201563	SCV000256374	pathogenic	Joubert syndrome 5	2015-02-23	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000502726	SCV000594072	pathogenic	Meckel syndrome, type 4	2016-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763314	SCV000893991	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816913	SCV000957442	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1465*) 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 (rs539400286, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 20683928, 29398085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217626). For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001030764	SCV001194259	pathogenic	Occipital encephalocele	2019-07-18	criteria provided, single submitter	clinical testing
DBGen Ocular Genomics	RCV001589085	SCV001816064	pathogenic	Leber congenital amaurosis 10	2021-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001529566	SCV002818938	pathogenic	not provided	2023-01-03	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17564967, 19764032, 20683928, 21962508, 22848652, 22995991, 26092869, 28157192, 29398085, 25525159, 33921607, 31589614, 34196201, 35005812)
Baylor Genetics	RCV003468919	SCV004216552	pathogenic	Bardet-Biedl syndrome 14	2024-03-14	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000201563	SCV004812276	pathogenic	Joubert syndrome 5	2022-06-02	criteria provided, single submitter	clinical testing	This sequence change in CEP290 is a nonsense variant predicted to cause a premature stop codon, p.(Arg1465*), in biologically relevant-exon X/Y leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v2.1 is 0.006% (2/35,222 alleles) in the Latino/admixed American population, which is consistent with recessive disease. This variant has been detected homozygous and compound heterozygous with a second allele in multiple individuals with ciliopathy phenotypes (PMID: 17564967, 20683928, 35005812). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3, PM2_Supporting.
Breakthrough Genomics, Breakthrough Genomics	RCV001589085	SCV005088754	pathogenic	Leber congenital amaurosis 10	2021-11-17	criteria provided, single submitter	clinical testing	This variant was previously reported in families with Joubert syndrome and Leber congenital amaurosis and observed to segregate with Leber congenital amaurosis. It has been observed in combination with another CEP290 variant in unrelated individuals affected with Leber congenital amaurosis [PMID: 29398085, 20683928]. Loss-of-function variants in the CEP290 gene are known to be pathogenic [PMID: 16909394, 17345604, 20690115].
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002937	SCV001160972	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001002937	SCV001452837	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529566	SCV001743212	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529566	SCV001930478	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529566	SCV001953346	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732782	SCV005365259	pathogenic	CEP290-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The CEP290 c.4393C>T variant is predicted to result in premature protein termination (p.Arg1465*). This variant has been reported in the homozygous state as causative for Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869), and in the compound heterozygous state as causative for Leber congenital amaurosis (Coppieters et al. 2010. PubMed ID: 20683928; Bravo-Gil et al. 2017. PubMed ID: 28157192; Sheck et al. 2018. PubMed ID: 29398085). This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.