Submissions for variant NM_000329.3(RPE65):c.295G>A (p.Val99Ile)

gnomAD frequency: 0.00009  dbSNP: rs143056561

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV004527403	SCV005038779	likely benign	RPE65-related recessive retinopathy	2024-02-19	reviewed by expert panel	curation	NM_000329.3(RPE65):c.295G>A is a missense variant causing substitution of valine with isoleucine at position 99. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.002650, with 68 alleles / 19954 total alleles in the East Asian population (with 2 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), extinguished electroretinogram responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), peripheral vision loss and (1 pt). However, the proband lacks the second variant required to apply the PP4 code. This variant has been reported in at least 4 probands with early-onset severe retinal dystrophy who harbored the variant in the heterozygous state (PMID: 21602930). However, the probands were not counted for PM3 because they lacked the second variant required to apply the code. The computational predictor REVEL gives a score of 0.517, which is below the ClinGen LCA / eoRD VCEP threshold of ≥0.644 and does not predict a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.10, which is below the ClinGen LCA / eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000972144	SCV001119838	likely benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097119	SCV001253373	likely benign	Leber congenital amaurosis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001097120	SCV001253374	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV004535963	SCV004114849	uncertain significance	RPE65-related disorder	2023-08-12	criteria provided, single submitter	clinical testing	The RPE65 c.295G>A variant is predicted to result in the amino acid substitution p.Val99Ile. This variant has been reported in the compound heterozygous state in individual with high hyperopia (Li et al. 2019. PubMed ID: 31273949). This variant is reported in 0.34% of alleles in individuals of East Asian descent in gnomAD, including two homozygous individuals (http://gnomad.broadinstitute.org/variant/1-68910517-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001275335	SCV001460409	likely benign	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing