ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.1338G>T (p.Arg446Ser) (rs1420672586)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cytogenetics and Genomics Laboratory,Medical University of South Carolina RCV000515733 SCV000803382 likely pathogenic Leber congenital amaurosis 2018-06-01 criteria provided, single submitter research
Invitae RCV001245608 SCV001418906 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 446 of the RPE65 protein (p.Arg446Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant also falls at the last nucleotide of exon 12 of the RPE65 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Leber congenital amaurosis (PMID: 26047050, 28714225, 30870047). 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: 427864). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28714225). For these reasons, this variant has been classified as Pathogenic.
Rui Chen Lab,Baylor College of Medicine RCV000515733 SCV000579419 pathogenic Leber congenital amaurosis 2017-05-09 no assertion criteria provided research

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