Submissions for variant NM_025114.4(CEP290):c.7328_7332del (p.Glu2443fs)

dbSNP: rs747138345

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001062455	SCV001227256	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Thr2457Alafs*27) have been determined to be pathogenic (PMID: 30193310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 856893). This variant is also known as c.7323_7327delAGAAG. This premature translational stop signal has been observed in individuals with CEP290-related conditions (PMID: 24850569, 28157192). This variant is present in population databases (rs747138345, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Glu2443Glyfs*11) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the CEP290 protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307671	SCV002600371	pathogenic	CEP290-related disorder	2022-10-09	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.7328_7332delAGAAG (p.Glu2443GlyfsX11) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Although the variant is not predicted to cause nonsense mediated decay, the variant disrupts the last 37 amino acids in the native protein sequence. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.7341_7344dup [p.Ser2449fs]). The variant allele was found at a frequency of 1.6e-05 in 246068 control chromosomes (gnomAD). c.7328_7332delAGAAG has been reported in the literature as a biallelic genotype in individuals affected with CEP290-Related Disorders (e.g. Bravo-Gil_2017, Takahashi_2019, Ganapathi_2022). 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. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505632	SCV002816237	pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2021-12-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467818	SCV004216630	pathogenic	Bardet-Biedl syndrome 14	2024-03-19	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004761917	SCV005374437	pathogenic	Leber congenital amaurosis 10	2024-09-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001827398	SCV002091808	pathogenic	Leber congenital amaurosis	2020-12-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV002307671	SCV005367274	pathogenic	CEP290-related disorder	2024-09-23	no assertion criteria provided	clinical testing	The CEP290 c.7328_7332del5 variant is predicted to result in a frameshift and premature protein termination (p.Glu2443Glyfs*11). This variant in compound heterozygous state has been reported in simplex retinitis pigmentosa and Joubert syndrome cases (Bravo-Gil et al. 2017. PubMed ID: 28157192; Wang et al. 2015. PubMed ID: 24850569). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as pathogenic.