Submissions for variant NM_000329.3(RPE65):c.119G>A (p.Gly40Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003133792	SCV003813981	likely pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778716	SCV004569680	likely pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-07-31	criteria provided, single submitter	clinical testing	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. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 40 of the RPE65 protein (p.Gly40Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive RPE65-related conditions (PMID: 28418496, 31630094). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2432988). This variant disrupts the p.Gly40 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9501220, 16150724, 19431183, 25257057, 29332120, 29785639). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.