Submissions for variant NM_025114.4(CEP290):c.7392_7393insCA (p.Glu2465fs)

dbSNP: rs757255407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241131	SCV001414126	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the CEP290 gene (p.Glu2465Glnfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the CEP290 protein and extend the protein by 5 additional amino acid residues. This variant is present in population databases (rs757255407, gnomAD 0.06%). 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: 966453). This variant disrupts the C-terminus of the CEP290 protein. Other variant(s) that disrupt this region (p.Glu2465Valfs*2) have been observed in individuals with CEP290-related conditions (PMID: 34196655). This suggests that this may be a clinically significant region of the protein. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001586081	SCV001813187	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in abnormal protein length as the last 15 amino acid(s) are replaced with 20 different amino acid(s), and other similar variants have been reported in HGMD; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34196655)
Natera, Inc.	RCV001828967	SCV002091802	uncertain significance	Leber congenital amaurosis	2020-01-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528434	SCV004108233	uncertain significance	CEP290-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The CEP290 c.7392_7393insCA variant is predicted to result in a frameshift and premature protein termination (p.Glu2465Glnfs*21). This variant is located in the last exon of coding and is expected to disrupt the final 16 amino acids. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.058% of alleles in individuals of African descent in gnomAD. Although frameshift variants are known to be pathogenic, nearly all occur upstream of this variant. Therefore, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.