Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000701390 | SCV000830190 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2023-08-02 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with Leber's congenital amaurosis (PMID: 11462243, 15024725, 18539930, 19431183, 20079931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16150724). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RPE65 protein function. ClinVar contains an entry for this variant (Variation ID: 98840). This variant is present in population databases (rs61751282, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 44 of the RPE65 protein (p.Arg44Gln). |
3billion | RCV001808321 | SCV002058435 | pathogenic | Retinitis pigmentosa 20 | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RPE65 related disorder (ClinVar ID: VCV000098840, PMID:11462243, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11462243, 15024725, 20079931, PM3_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16150724, 19431183, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3CNET: 0.813, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 20 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M).. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Prevention |
RCV004528783 | SCV004109643 | pathogenic | RPE65-related disorder | 2023-04-20 | criteria provided, single submitter | clinical testing | The RPE65 c.131G>A variant is predicted to result in the amino acid substitution p.Arg44Gln. This variant in either homozygous state or along with a second causative variant, has been reported in patients with RPE65-associated disorders such as Leber congenital amaurosis (Simovich et al. 2001. PubMed ID: 11462243; Table S1, Patel. 2016. PubMed ID: 26355662; Cideciyan et al. 2008. PubMed ID: 18809924). Functional in vitro studies have shown that this variant resulted in a protein with reduced isomerization activity (~2% of wild-type activity) (Redmond. 2005. PubMed ID: 16150724; Philp. 2009. PubMed ID: 19431183). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-68912507-C-T). This variant is interpreted as pathogenic. |
Baylor Genetics | RCV001250676 | SCV004209226 | pathogenic | Leber congenital amaurosis 2 | 2023-10-04 | criteria provided, single submitter | clinical testing | |
Retina International | RCV000085166 | SCV000117303 | not provided | not provided | no assertion provided | not provided | ||
Laboratory of Genetics in Ophthalmology, |
RCV001250676 | SCV001425546 | likely pathogenic | Leber congenital amaurosis 2 | no assertion criteria provided | research | ||
Faculty of Health Sciences, |
RCV001257816 | SCV001434600 | pathogenic | Autosomal recessive retinitis pigmentosa | 2015-09-10 | no assertion criteria provided | literature only | |
Natera, |
RCV001275338 | SCV001460412 | pathogenic | Leber congenital amaurosis | 2020-09-16 | no assertion criteria provided | clinical testing |