Submissions for variant NM_025114.4(CEP290):c.7341_7344dup (p.Ser2449fs)

gnomAD frequency: 0.00001  dbSNP: rs778907433

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001030765	SCV001194260	likely pathogenic	Rod-cone dystrophy	2017-09-03	criteria provided, single submitter	clinical testing
Invitae	RCV001231786	SCV001404318	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2019-11-11	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with CEP290-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the CEP290 gene (p.Ser2449Thrfs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acids of the CEP290 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CEP290 protein. Other variant(s) that disrupt this region (p.Thr2457Alafs*27) have been determined to be pathogenic (PMID: 30193310). This suggests that variants that disrupt this region of the protein are likely to be causative of disease.