Submissions for variant NM_152443.3(RDH12):c.617C>A (p.Ala206Asp)

dbSNP: rs1254096311

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003463499	SCV004208622	likely pathogenic	Leber congenital amaurosis 13	2021-11-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003463499	SCV004297107	likely pathogenic	Leber congenital amaurosis 13	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 206 of the RDH12 protein (p.Ala206Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive retinal dystrophy (PMID: 16269441). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 expected to disrupt RDH12 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). This variant disrupts the p.Ala206 amino acid residue in RDH12. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30902645). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701069	SCV005203684	likely pathogenic	Leber congenital amaurosis	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.617C>A (p.Ala206Asp) 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 was absent in 251076 control chromosomes. c.617C>A has been reported in the literature in the presumed compound heterozygous state in at least 2 related individuals affected with autosomal recessive Leber Congenital Amaurosis (example, Jacobson_2007, Thompson_2005), include at least 1 individual carrying a pathogenic variant in trans. These data indicate that the variant may be associated with disease. At least one publication reports in vitro experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example Thompson_2005). The following publications have been ascertained in the context of this evaluation (PMID: 17197551, 16269441). ClinVar contains an entry for this variant (Variation ID: 2678309). Based on the evidence outlined above, the variant was classified as likely pathogenic.