Submissions for variant NM_025114.4(CEP290):c.7282_7286dup (p.Tyr2429Ter)

dbSNP: rs2136546576

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272835	SCV002557239	pathogenic	Joubert syndrome 5	2022-06-24	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), Senior-Loken syndrome 6 (MIM#610189). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variants that have alternative nucleotide changes but result in the same p.(Y2429*) are present in gnomAD (v2) <0.01 for a recessive condition (total alleles: 11 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is predicted to truncate the last 51 amino acids of the protein (DECIPHER). (I) 0701 - Other truncated variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This exact variant is not reported. However two other variants which result in the same protein change (c.7287T>A; p.(Y2429*) and c.7283_7286dup; p.(Y2429*)) have been reported as likely pathogenic and pathogenic (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101543	SCV003318450	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-05-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2429*) 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. This variant disrupts a region of the CEP290 protein in which other variant(s) (p.Leu2448Thrfs*8) have been determined to be pathogenic (PMID: 16682973, 16909394, 29588463). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.