ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.893del (p.Lys298fs) (rs61752902)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414568 SCV000490776 pathogenic not provided 2018-09-21 criteria provided, single submitter clinical testing The c.893delA variant in the RPE65 gene has been reported previously in association with Leber Congenital Amaurosis (LCA) (Zernant et al., 2005; Stone et al., 2007; Lotery et al., 2000; Simovich et al., 2001; Wang et al., 2014). The deletion causes a frameshift starting with codon Lysine 298, changes this amino acid to a Serine residue and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Lys298SerfsX27. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret c.893delA as pathogenic.
Blueprint Genetics RCV001074534 SCV001240123 pathogenic Retinal dystrophy 2018-02-05 criteria provided, single submitter clinical testing
Invitae RCV001225799 SCV001398091 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2019-10-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys298Serfs*27) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs757246161, ExAC 0.003%). This variant has been observed in individual(s) affected with Leber congenital amaurosis (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372493). 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. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 18632300). For these reasons, this variant has been classified as Pathogenic.
Retina International RCV000414568 SCV000117365 not provided not provided no assertion provided not provided

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