Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003764791 | SCV004697425 | pathogenic | RPE65-related recessive retinopathy | 2024-02-20 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.272G>A (p.Arg91Gln) is a missense variant that replaces arginine with glutamine at position 91 in RPE65. At least one proband harboring this variant has been genotyped by next-generation sequencing analysis of 586 candidate genes without an alternative explanation for visual impairment (2 pts), with phenotypes including congenital onset (1 pt), abnormal best corrected visual acuity test (1 pt), extinguished scotopic (0.5 pts) and photopic (1 pt) electroretinogram responses, bone spicule pigmentation (0.5 pts), white or yellow dots in the fundus (2 pts), and nystagmus (1 pt), which together are highly specific for RPE65-related recessive retinopathy (9 points, PP4_Moderate). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.1022T>C (p.Leu341Ser) variant or the c.370C>T (p.Arg124Ter) variant suspected in trans (1 point, PMID: 32865313, PMID: 27102010), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP. This variant has also been reported in the homozygous state in at least 2 probands with early-onset severe retinal dystrophy (1 point, PMID: 32865313, PMID: 34492281; 2 total points, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through a proband plus 1 similarly affected relative, both of whom harbor the variant present in the compound heterozygous state with the c.725+4A>G variant confirmed in trans (PP1; PMID: 11462243). This variant is present in gnomAD v.2.1.1 at a Grpmax allele frequency of 0.0001609, with 8 alleles / 24940 total alleles in the African / African-American population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The computational predictor REVEL gives a score of 0.659, which is above the ClinGen LCA / eoRD VCEP threshold of >= 0.644 and predicts a damaging effect on RPE65 function (PP3). The variant also exhibited 1.33% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, Table 2, PMID: 19431183). Two other missense variants encoding different amino acid substitutions at the same codon have been reported in association with RPE65-related recessive retinopathy (PMID: 17724218, PMID: 9501220). However, c.271C>T (p.Arg91Trp) and c.272G>C (p.Arg91Pro) have not yet been classified by the ClinGen LCA / eoRD VCEP, and PM5 was not considered to avoid circularity. In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3, PP4_Moderate (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
Invitae | RCV001061074 | SCV001225805 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 91 of the RPE65 protein (p.Arg91Gln). This variant is present in population databases (rs61752873, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive Leber congenital amaurosis or retinitis pigmentosa (PMID: 11462243, 17197551, 18539930, 20079931, 25356976, 26656277, 30268864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98857). 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 not expected to disrupt RPE65 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 19431183). This variant disrupts the p.Arg91 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9501220, 10766140, 10937591, 11095629, 16754667, 18682808, 25752820). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Institute of Medical Genetics and Applied Genomics, |
RCV001731373 | SCV001983387 | pathogenic | Retinitis pigmentosa | 2021-10-25 | criteria provided, single submitter | clinical testing | |
Mendelics | RCV002247485 | SCV002518987 | pathogenic | Leber congenital amaurosis 2 | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000085186 | SCV002538895 | pathogenic | not provided | 2023-08-19 | criteria provided, single submitter | clinical testing | Published functional studies demonstrated a greatly reduced retinoid isomerase activity (Philp et al., 2009); This variant is associated with the following publications: (PMID: 11462243, 25356976, 25525159, 11095629, 31054281, 19431183, 26656277, 32865313, 34492281, 33952291, 17197551, 20079931, 31630094, 30996589, 34830511, 30268864, 18539930, 17651254, 16754667, 16518657, 19117922) |
Ambry Genetics | RCV003242980 | SCV003940539 | pathogenic | Inborn genetic diseases | 2023-06-12 | criteria provided, single submitter | clinical testing | The c.272G>A (p.R91Q) alteration is located in coding exon 4 of the RPE65 gene. This alteration results from a G to A substitution at nucleotide position 272, causing the arginine (R) at amino acid position 91 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.005% (13/282622) total alleles studied. The highest observed frequency was 0.032% (8/24940) of African alleles. This variant has been reported in numerous individuals diagnosed with a RPE65-related retinopathy in both homozygous and compound heterozygous states (Sallum, 2020; Lopez-Rodriguez, 2021; Shi, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
Baylor Genetics | RCV002247485 | SCV004209241 | pathogenic | Leber congenital amaurosis 2 | 2023-09-01 | criteria provided, single submitter | clinical testing | |
Retina International | RCV000085186 | SCV000117323 | not provided | not provided | no assertion provided | not provided | ||
Natera, |
RCV001275336 | SCV001460410 | pathogenic | Leber congenital amaurosis | 2020-09-16 | no assertion criteria provided | clinical testing |