Submissions for variant NM_000329.3(RPE65):c.242G>T (p.Arg81Ile) (rs1429137932)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cytogenetics and Genomics Laboratory,Medical University of South Carolina	RCV000754977	SCV000803387	likely pathogenic	Leber congenital amaurosis	2018-06-01	criteria provided, single submitter	research
Invitae	RCV001053470	SCV001217734	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2019-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with isoleucine at codon 81 of the RPE65 protein (p.Arg81Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Leber congenital amaurosis in families (PMID: 30870047). ClinVar contains an entry for this variant (Variation ID: 559523). 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina	RCV001098872	SCV001255269	uncertain significance	Leber congenital amaurosis 2	2018-02-16	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina	RCV001098873	SCV001255270	uncertain significance	Retinitis pigmentosa	2018-02-16	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.