Submissions for variant NM_000329.3(RPE65):c.540C>A (p.His180Gln)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586291	SCV005077185	likely pathogenic	Leber congenital amaurosis	2024-04-19	criteria provided, single submitter	clinical testing	Variant summary: RPE65 c.540C>A (p.His180Gln) results in a non-conservative amino acid change in the encoded protein sequence, which affects an iron binding His residue (Takahashi_2005, Redmond_2005). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251156 control chromosomes (gnomAD v2.1). c.540C>A has been reported in the literature in a compound heterozygous individual affected with Leber Congenital Amaurosis (Khan_2014), who carried a pathogenic variant in trans. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, publications reported experimental alanine mutagenesis of His residues which form the iron-binding pocket (His180, His241, His313, His527) of the protein, all abolished enzymatic activity (Takahashi_2005, Redmond_2005), supporting a critical role for these residues in protein function. The following publications have been ascertained in the context of this evaluation (PMID: 24997176, 16198348, 16150724). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.