ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.499G>T (p.Asp167Tyr) (rs61752883)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085203 SCV000491115 likely pathogenic not provided 2016-08-03 criteria provided, single submitter clinical testing The D167Y variant in the RPE65 gene has been reported previously in the heterozygous state along with a second RPE65 variant in a few unrelated individuals with retinal dystrophy and Leber congenital amaurosis; however, the phase of the variants was not confirmed in all cases (Thompson et al., 2000; Simonelli et al., 2007; Henderson et al., 2007; Ripamonti et al., 2014). The D167Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D167Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D167Y as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778252 SCV000914424 likely pathogenic RPE65-Related Disorders 2018-12-11 criteria provided, single submitter clinical testing The RPE65 c.499G>T (p.Asp167Tyr) variant is a missense variant that has been reported in a compound heterozygous state in three individuals with either Leber congenital amaurosis or retinal dystrophy (Thompson et al. 2000; Simonelli et al. 2007; Bainbridge et al. 2008; Ripamonti et al. 2014). The p.Asp167Tyr variant was also identified in a heterozygous state in one additional case in whom a second variant was not identified (Henderson et al. 2007). The p.Asp167Tyr variant was absent from 50 control individuals but was reported at a frequency of 0.000026 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies of this variant have not been conducted, but it affects a conserved residue and in silico tools predict it to have a damaging effect. Based on the collective evidence, the p.Asp167Tyr variant is classified as likely pathogenic for RPE65-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001245153 SCV001418423 likely pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 167 of the RPE65 protein (p.Asp167Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs61752883, ExAC 0.002%). This variant has been observed in individual(s) with retinal dystrophy (PMID: 11095629, 17724218, 18441371, 25257057). ClinVar contains an entry for this variant (Variation ID: 98873). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Retina International RCV000085203 SCV000117340 not provided not provided no assertion provided not provided
Human Genetics - Radboudumc,Radboudumc RCV000678617 SCV000804705 uncertain significance Retinitis pigmentosa 20 2016-09-01 no assertion criteria provided clinical testing
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV001250708 SCV001425586 likely pathogenic Leber congenital amaurosis 2 no assertion criteria provided research

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