Submissions for variant NM_000329.3(RPE65):c.3G>A (p.Met1Ile)

dbSNP: rs1357241537

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379122	SCV001576863	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-02-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RPE65 protein in which other variant(s) (p.Pro25Leu) have been determined to be pathogenic (PMID: 18599565, 25972377, 28041643, 30268864). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1067769). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 9501220). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects the initiator methionine of the RPE65 mRNA. The next in-frame methionine is located at codon 93.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801002	SCV005423256	likely pathogenic	Leber congenital amaurosis	2024-10-15	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in frame methionine occurs at p.Met93. Two of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251304 control chromosomes. To our knowledge, no occurrence of c.3G>A in individuals affected with Leber Congenital Amaurosis and no experimental evidence demonstrating its impact on protein function have been reported. A downstream missense variant has been classified as Pathogenic by our lab (p.Leu22Pro), suggesting this region of the protein is essential. ClinVar contains an entry for this variant (Variation ID: 1067769). Based on the evidence outlined above, the variant was classified as likely pathogenic.