Submissions for variant NM_152443.3(RDH12):c.139G>A (p.Ala47Thr)

gnomAD frequency: 0.00003  dbSNP: rs761231974

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001057696	SCV001222200	pathogenic	Leber congenital amaurosis 13	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 47 of the RDH12 protein (p.Ala47Thr). This variant is present in population databases (rs761231974, gnomAD 0.003%). This missense change has been observed in individual(s) with Leber congenital amaurosis and cone-rod dystrophy (PMID: 16269441, 17197551, 23105016, 26355662, 30134391). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 852972). 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 RDH12 protein function. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001057696	SCV001573404	likely pathogenic	Leber congenital amaurosis 13	2021-04-08	criteria provided, single submitter	research	The RDH12 c.139G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PS3. Based on this evidence we have classified this variant as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420746	SCV001623089	pathogenic	Leber congenital amaurosis	2021-04-21	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.139G>A (p.Ala47Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251486 control chromosomes (gnomAD). c.139G>A has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis or retinal dystrophy or Retinitis pigmentosa & Rod cone dystrophy (Thompson_2005, Abu-Safieh_2013, Patel_2015). These data indicate that the variant is very likely to be associated with disease. In in vitro functional assays, the variant showed reduced ability to convert all-trans retinal to all-trans retinol exhibiting approximately 10% of wild-type activity (Thompson_2005). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001057696	SCV004208591	pathogenic	Leber congenital amaurosis 13	2023-07-25	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001057696	SCV004801131	pathogenic	Leber congenital amaurosis 13	2024-02-11	criteria provided, single submitter	research
Natera, Inc.	RCV001420746	SCV002091251	pathogenic	Leber congenital amaurosis	2020-05-05	no assertion criteria provided	clinical testing