Submissions for variant NM_025114.4(CEP290):c.2722C>T (p.Arg908Ter)

gnomAD frequency: 0.00003  dbSNP: rs886042153

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000382757	SCV000332186	pathogenic	not provided	2015-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000988885	SCV001138783	pathogenic	Joubert syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380938	SCV001579164	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg908*) 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 (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cone-rod dystrophy (PMID: 30718709). ClinVar contains an entry for this variant (Variation ID: 281411). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222465	SCV002500761	pathogenic	CEP290-related disorder	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.2722C>T (p.Arg908X) 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 1.2e-05 in 242780 control chromosomes (gnomAD). c.2722C>T has been reported in the literature in individuals affected with CEP290-Related Disorders (examples: Huang_2018 and Sallum_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002479997	SCV002784016	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2024-02-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000382757	SCV004022857	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	Identified in a patient with cone-rod dystrophy in published literature, however no second CEP290 variant was identified (PMID: 30718709); 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30718709, 32865313)
Neuberg Centre For Genomic Medicine, NCGM	RCV003447521	SCV004175751	pathogenic	Joubert syndrome 5	2023-03-01	criteria provided, single submitter	clinical testing	The stop gained c.2722C>T(p.Arg908Ter) variant in CEP290 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with retinal dystrophy (Jespersgaard et al., 2019). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP290 are known to be pathogenic (Coppieters et al., 2010). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
Baylor Genetics	RCV003469220	SCV004216643	pathogenic	Bardet-Biedl syndrome 14	2024-02-21	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816477	SCV005072568	pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787815	SCV000926825	likely pathogenic	Cone-rod dystrophy	2018-04-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV002222465	SCV004115508	pathogenic	CEP290-related disorder	2024-08-11	no assertion criteria provided	clinical testing	The CEP290 c.2722C>T variant is predicted to result in premature protein termination (p.Arg908*). This variant has been reported along with a second plausible causative variant in three patients, one diagnosed with Leber congenital amaurosis and two diagnosed with Joubert syndrome (Sallum et al. 2020. PubMed ID: 32865313). This variant is reported in 0.0057% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.