Submissions for variant NM_025114.4(CEP290):c.6798G>A (p.Trp2266Ter)

gnomAD frequency: 0.00002  dbSNP: rs760540562

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596012	SCV000702706	pathogenic	not provided	2016-11-18	criteria provided, single submitter	clinical testing
Invitae	RCV000636987	SCV000758435	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2266*) 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 (rs760540562, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 497937). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV002250666	SCV002521219	pathogenic	Leber congenital amaurosis 10	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000497937). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282253	SCV002570952	pathogenic	CEP290-Related Disorders	2022-07-20	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.6798G>A (p.Trp2266X) 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 0.00013 in 251868 control chromosomes (gnomAD and Kausthubham_2021). It is seen predominantly within the East Asian subpopulation in the gnomAD database at a frequency of 0.0017, and has been reported at a frequency of 0.0025 in Han Chinese population (Wei_2021). However, this frequency allows no specific conclusions to be made about variant significance. c.6798G>A has been reported in the literature in at least one individual affected with Leber congenital amaurosis (e.g. Zhu_2021) and in compound heterozygous individuals with clinical symptoms such as episodic ataxia and retinal dystrophy (e.g.Hamed_2020, Hull_2020), which are features of some CEP290-Related Disorders. These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294351	SCV002587479	pathogenic	Kidney disorder	2021-06-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002506412	SCV002808551	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2022-01-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003459464	SCV004214832	pathogenic	Bardet-Biedl syndrome 14	2023-10-26	criteria provided, single submitter	clinical testing