Submissions for variant NM_000329.3(RPE65):c.48T>C (p.Phe16=)

gnomAD frequency: 0.00059  dbSNP: rs62642581

Total submissions: 10

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	RCV004527315	SCV005038771	likely benign	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.48T>C (p.Phe16=) is a synonymous (silent) variant in exon 2. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.001007, with 1250 alleles/1179940 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The REVEL score for this variant is 0, which is below the ClinGen LCA/eoRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPE65 function. Additionally, the splicing impact predictor, SpliceAI, gives a score of 0.01, 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 likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Illumina Laboratory Services, Illumina	RCV000296314	SCV000358886	uncertain significance	Retinitis pigmentosa	2018-01-12	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 Laboratory Services, Illumina	RCV000332977	SCV000358887	uncertain significance	Leber congenital amaurosis 2	2018-01-12	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.
Counsyl	RCV000674828	SCV000800229	likely benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2018-05-29	criteria provided, single submitter	clinical testing
Invitae	RCV000674828	SCV001020674	benign	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000085201	SCV001912199	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Retina International	RCV000085201	SCV000117338	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV001275290	SCV001460290	likely benign	Leber congenital amaurosis	2020-06-05	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699122	SCV001918273	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085201	SCV001974921	likely benign	not provided		no assertion criteria provided	clinical testing