ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.131G>C (p.Arg44Pro)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003088739 SCV003486825 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2024-07-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 44 of the RPE65 protein (p.Arg44Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Leber congenital amaurosis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2170981). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPE65 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg44 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11462243, 15024725, 16150724, 18539930, 19431183, 20079931). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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