Submissions for variant NM_000329.3(RPE65):c.1302G>A (p.Ala434=)

dbSNP: rs62636301

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	RCV003459236	SCV004190219	benign	RPE65-related recessive retinopathy	2023-12-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1302G>A (p.Ala434=) is a synonymous variant that is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.02695, with 734 alleles / 24954 total alleles and 7 homozygotes in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The splicing impact predictor SpliceAI gives a delta score of 0.07 for donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Invitae	RCV000549727	SCV000644180	benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000549727	SCV000795605	likely benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2017-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001096915	SCV001253161	likely benign	Retinitis pigmentosa	2017-04-28	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001096916	SCV001253162	likely benign	Leber congenital amaurosis 2	2017-04-28	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Natera, Inc.	RCV001273330	SCV001456289	benign	Leber congenital amaurosis	2020-09-16	no assertion criteria provided	clinical testing