Submissions for variant NM_025114.4(CEP290):c.1666del (p.Ile556fs)

dbSNP: rs727503855

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201771	SCV000256368	pathogenic	Joubert syndrome 5	2015-02-23	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000697843	SCV000826475	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile556Phefs*17) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 26047050, 26092869, 27491411). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217622). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000988888	SCV001138786	pathogenic	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075310	SCV001240928	pathogenic	Retinal dystrophy	2017-12-29	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268720	SCV001447853	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376373	SCV001573491	pathogenic	Leber congenital amaurosis 10	2021-04-08	criteria provided, single submitter	research	The CEP290 c.1666del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS3. Based on this evidence we have classified this variant as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500629	SCV002811713	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2021-08-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001268720	SCV003820650	pathogenic	not provided	2022-01-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468916	SCV004214856	pathogenic	Bardet-Biedl syndrome 14	2024-02-23	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001376373	SCV005088736	pathogenic	Leber congenital amaurosis 10	2021-08-03	criteria provided, single submitter	clinical testing	This variant was previously reported in individuals with Joubert syndrome and observed to segregate with disease in related individuals [PMID: 26047050, 26092869, 27491411]. Loss-of-function variants in the CEP290 gene are reported to be pathogenic [PMID: 16909394, 17345604, 20690115].
GeneDx	RCV001268720	SCV005202133	pathogenic	not provided	2023-12-12	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; This variant is associated with the following publications: (PMID: 31589614, 21228398, 17564967, 27491411, 26047050, 29641573, 26092869, 32165824, 35627109, 29771326, 31630094, 36460718, 34906470, 36729443, 32507488, 33970760, 31087526, 36819107, 33576794, 32865313, 34196655)
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000201771	SCV005375243	pathogenic	Joubert syndrome 5	2024-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (GRCh38; NM_025114.4:c.1666del:p.Ile556PhefsTer17) in the CEP290 protein. This alteration is expected to result in loss of function by premature termination codon resulting in protein truncation, or nonsense-mediated mRNA decay. This alteration is interpreted as disease-causing mutation, a commonly known mechanism for disease. Well-established in-vitro or in-vivo functional studies supportive of a damaging effect on the gene or gene product PMID: 29771326 ClinVar contains an entry for this variant (Variation ID: 217622). This variant is associated with the following publications: PubMed: 26047050, 17564967, 26092869, 29771326, 27491411 In summary, this variant meets our criteria for classification as pathogenic based on the evidence outlined.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002938	SCV001160973	pathogenic	Leber congenital amaurosis	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001002938	SCV001457923	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732780	SCV005352011	pathogenic	CEP290-related disorder	2024-04-15	no assertion criteria provided	clinical testing	The CEP290 c.1666delA variant is predicted to result in a frameshift and premature protein termination (p.Ile556Phefs*17). This variant in the homozygous or compound heterozygous state has been reported to be causative for CEP290-related disorders (Brancati et al. 2007. PubMed ID: 17564967; Wang et al. 2015. PubMed ID: 26047050; Zhu et al. 2021. PubMed ID: 33970760). This variant had been reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD 2.1.1 (as displayed in the table above). However, due to technical limitations, these numbers were not reliable. With a higher quality data in gnomAD V4 dataset, this variant has been identified at a maximum frequency of 0.0457% of alleles in individuals of South Asian descent. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.