ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.952T>A (p.Tyr318Asn)

gnomAD frequency: 0.00003  dbSNP: rs61752905
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV001089895 SCV001245402 likely pathogenic Leber congenital amaurosis 2 2020-02-14 criteria provided, single submitter curation This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3.
Invitae RCV001854499 SCV002265097 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2023-10-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 318 of the RPE65 protein (p.Tyr318Asn). This variant is present in population databases (rs61752905, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive Leber congenital amaurosis and/or retinitis pigmentosa (PMID: 29332120; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 98900). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPE65 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 19431183, 24849605). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323394 SCV004028604 pathogenic Leber congenital amaurosis 2023-07-19 criteria provided, single submitter clinical testing Variant summary: RPE65 c.952T>A (p.Tyr318Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251368 control chromosomes. c.952T>A has been reported in the literature in the compound heterozygous state together with a pathogenic variant in at least three individuals affected with Leber Congenital Amaurosis or an inherited retinal disease (e.g. Weleber_2016, Kumaran_2018, Sheck_2021) and has been reported as an unspecified genotype in an individual in a Leber Congenital Amaurosis cohort (Stone_2007). These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and both found the variant had decreased protein expression levels and resulted in <10% of normal activity (e.g. Philip_2009, Li_2014). The following publications have been ascertained in the context of this evaluation (PMID: 30268864, 29332120, 24849605, 19431183, 33749171, 17964524, 27102010, 16123401). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV001089895 SCV004209234 pathogenic Leber congenital amaurosis 2 2023-09-12 criteria provided, single submitter clinical testing
Retina International RCV000085233 SCV000117370 not provided not provided no assertion provided not provided
Laboratory of Genetics in Ophthalmology, Institut Imagine RCV001089895 SCV001425562 likely pathogenic Leber congenital amaurosis 2 no assertion criteria provided research

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