ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.118G>A (p.Gly40Ser) (rs61751281)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085155 SCV000329701 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing The G40S variant in the RPE65 gene has been reported previously, in the homozygous or compound heterozygous state, in unrelated individuals with Leber congenital amaurosis (Morimura et al.,1998; Galvin et al., 2005; Jacobson et al., 2009; Pasadhika et al., 2010; Ripamonti et al., 2014). The G40S 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 G40S 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 vitro functional studies demonstrated that the G40S variant results in a significant reduction in isomerization acitivity and significant reduction in protein expression (Redmond et al., 2005; Li et al., 2014). Therefore, we interpret G40S as a pathogenic variant.
Invitae RCV001047503 SCV001211466 pathogenic Leber congenital amaurosis 2; Retinitis pigmentosa 20 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 40 of the RPE65 protein (p.Gly40Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with RPE65-related disease (PMID: 9501220, 29785639, 25257057, 29332120). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98830). This variant has been reported to affect RPE65 protein function (PMID: 16150724, 19431183). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074416 SCV001239998 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
Retina International RCV000085155 SCV000117292 not provided not provided no assertion provided not provided
Department of Ophthalmology and Visual Sciences Kyoto University RCV000132582 SCV000172525 pathogenic Retinitis pigmentosa no assertion criteria provided not provided Converted during submission to Pathogenic.
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV001250675 SCV001425545 pathogenic Leber congenital amaurosis 2 no assertion criteria provided research

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