Submissions for variant NM_025114.4(CEP290):c.7282_7283dup (p.Tyr2429fs)

gnomAD frequency: 0.00002  dbSNP: rs767231715

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389629	SCV001591055	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2023-09-12	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: 1075924). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. This variant is present in population databases (rs767231715, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr2429Serfs*8) in the CEP290 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the CEP290 protein.
Baylor Genetics	RCV003463031	SCV004214845	likely pathogenic	Bardet-Biedl syndrome 14	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479322	SCV004223394	pathogenic	CEP290-related disorder	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: CEP290 c.7282_7283dupAA (p.Tyr2429SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 8.5e-06 in 235560 control chromosomes (gnomAD). To our knowledge, no occurrence of c.7282_7283dupAA in individuals affected with CEP290-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005005242	SCV005630343	likely pathogenic	Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14	2024-05-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003479322	SCV005362460	likely pathogenic	CEP290-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The CEP290 c.7282_7283dupAA variant is predicted to result in a frameshift and premature protein termination (p.Tyr2429Serfs*8). To our knowledge, this variant has not been reported in the literature. Although this variant is located in the last exon of CEP290, other protein-truncating variants both 5' and 3' this variant have been reported to be causative for autosomal recessive CEP290 disease (Halbritter et al. 2013. PubMed ID: 23559409; Wang et al. 2015. PubMed ID: 24850569). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CEP290 are expected to be pathogenic. This variant is interpreted as likely pathogenic.