Submissions for variant NM_025114.4(CEP290):c.5493del (p.Ala1832fs)

dbSNP: rs386834158

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000392172	SCV000339354	pathogenic	not provided	2016-02-12	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415183	SCV000493057	pathogenic	Familial aplasia of the vermis; Polycystic kidney disease; Abnormality of the kidney; Cerebellar vermis hypoplasia; Cerebellar cyst; Hyperechogenic kidneys	2014-01-29	criteria provided, single submitter	clinical testing
Invitae	RCV000815718	SCV000956184	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1832Profs*19) 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 Leber congenital amaurosis and/or Meckel-Gruber syndrome (PMID: 17705300, 20683928, 21245082). This variant is also known as 5489_5493delA, c.5489del and p.Gln1830fs. ClinVar contains an entry for this variant (Variation ID: 56739). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000392172	SCV001168591	pathogenic	not provided	2019-01-23	criteria provided, single submitter	clinical testing	The c.5493delA pathogenic variant in the CEP290 gene has been reported previously in association with CEP290-related disorders (Tallila et al., 2009; Travaglini et al., 2009; Cideciyan et al., 2011). The deletion causes a frameshift starting with codon Alanine 1832, changes this amino acid to a Proline residue and creates a premature Stop codon at position 19 of the new reading frame, denoted p.Ala1832ProfsX19. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5493delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198221	SCV001369091	pathogenic	Joubert syndrome 5	2019-07-09	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000392172	SCV001447708	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000050152	SCV001467941	pathogenic	Meckel syndrome, type 4	2020-12-07	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.5493delA (p.Ala1832ProfsX19) 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 2.2e-05 in 223598 control chromosomes. c.5493delA has been reported in the literature in individuals affected with Joubert syndromerelated disorders, retinal dystrophy, or Leber congenital amaurosis (Brancati_2007, Carss_2017, Feldhaus_2020). These data indicate that the variant may be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376199	SCV001573254	pathogenic	Leber congenital amaurosis 10	2021-04-08	criteria provided, single submitter	research	The CEP290 c.5493del 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: PM2, PP1, PVS1. Based on this evidence we have classified this variant as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001198221	SCV001950046	pathogenic	Joubert syndrome 5	2021-04-08	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_025114.4:c.2279_2280del.
CeGaT Center for Human Genetics Tuebingen	RCV000392172	SCV001961367	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CEP290: PVS1, PM2, PM3
New York Genome Center	RCV002467561	SCV002764401	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5	2021-10-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147336	SCV003836220	pathogenic	CEP290-Related Disorders	2022-05-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460647	SCV004214849	pathogenic	Bardet-Biedl syndrome 14	2023-10-20	criteria provided, single submitter	clinical testing
OMIM	RCV000050152	SCV000021559	pathogenic	Meckel syndrome, type 4	2008-01-01	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050152	SCV000082562	probable-pathogenic	Meckel syndrome, type 4		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504936	SCV000599191	pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001276488	SCV001462867	pathogenic	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing