ClinVar Miner

Submissions for variant NM_000329.3(RPE65):c.131G>A (p.Arg44Gln)

gnomAD frequency: 0.00004  dbSNP: rs61751282
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Total submissions: 8
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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.
PreventionGenetics, part of Exact Sciences 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 ( 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, Institut Imagine RCV001250676 SCV001425546 likely pathogenic Leber congenital amaurosis 2 no assertion criteria provided research
Faculty of Health Sciences, Beirut Arab University RCV001257816 SCV001434600 pathogenic Autosomal recessive retinitis pigmentosa 2015-09-10 no assertion criteria provided literature only
Natera, Inc. RCV001275338 SCV001460412 pathogenic Leber congenital amaurosis 2020-09-16 no assertion criteria provided clinical testing

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