Submissions for variant NM_025114.4(CEP290):c.451C>T (p.Arg151Ter)

gnomAD frequency: 0.00001  dbSNP: rs757641323

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414162	SCV000491224	pathogenic	not provided	2016-10-11	criteria provided, single submitter	clinical testing	The R151X variant in the CEP290 gene has been reported previously in association with Leber congenital amaurosis, early-onset severe retinal dystrophy, and a nonspecified retinal dystrophy (Littink et al., 2010; Huang et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R151X variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Based on currently available evidence, we interpret R151X as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552078	SCV000634657	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg151*) in the CEP290 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. 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 retinal dystrophy (PMID: 20130272, 25356976, 28829391; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372761). Studies have shown that this premature translational stop signal results in skipping of exon 7 or exons 7-8, but is expected to preserve the integrity of the reading-frame (PMID: 20130272). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000999862	SCV000885166	likely pathogenic	not specified	2018-07-09	criteria provided, single submitter	clinical testing	The CEP290 c.451C>T;p.Arg151Ter variant has been described in at least one individual with retinal dystrophy (Huang 2015) and one family with early onset severe retinal dystrophy and Leber congential amaurosis (Littink 2010). The variant is listed in the ClinVar database (Variation ID: 372761) and the dbSNP variant database (rs757641323) but is not listed in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, but at least one report shows that this variant leads to a skipping of exon 7 or exon 7 and 8, which leads to an in-frame product lacking a portion of a functional domain. Considering available information, this variant is classified as likely pathogenic. References: Huang XF et al. Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing. Genet Med. 2015 Apr;17(4):271-8. Littink KW et al. A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3646-52.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470852	SCV002767038	pathogenic	Leber congenital amaurosis 10	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 5 (MIM#610188), Leber congenital amaurosis 10 (MIM#611755), Meckel syndrome 4 (MIM#611134) and Senior-Loken syndrome 6 (MIM#610189). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR experiments using patient cDNA have demonstrated that this variant results in in-frame skipping of either exon 7 (p.(Leu148_Glu165del)) or exon 7 and exon 8 (p.(Leu148_Lys172del)) (PMIDs: 20130272, 28829391). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and has been reported as compound heterozygous in multiple individuals with Leber congenital amaurosis, early-onset severe retinal dystrophy or oligocone trichromacy (PMIDs: 20130272, 28829391, 25356976, 27208204). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_025114.3(CEP290):c.2506G>T; p.(Glu836*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003463818	SCV004214841	pathogenic	Bardet-Biedl syndrome 14	2024-02-20	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000414162	SCV001958420	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000414162	SCV001967655	pathogenic	not provided		no assertion criteria provided	clinical testing