ClinVar Genomic variation as it relates to human health

The PDE6A c.304C>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: PS1, PM2, PP1. Based on this evidence we have classified this variant as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 102 of the PDE6A protein (p.Arg102Ser). This variant is present in population databases (rs141252097, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (arRP) (PMID: 10393062, 25775262, 26868535, 27917291). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 193099). 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 PDE6A protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The PDE6A c.304C>A (p.Arg102Ser) missense variant has been reported in several studies. The variant was first reported by Dryja et al. (1999), who identified the variant in a compound heterozygous state in a sibling pair affected with autosomal recessive retinitis pigmentosa (arRP) and in a heterozygous state in the unaffected father and an unaffected sibling. Maria et al. (2015) later reported the variant in a homozygous state in a total of five individuals, including two sibling pairs, from a large consanguineous family affected with arRP. The variant was also identified in a heterozygous state in nine unaffected family members. The p.Arg102Ser variant has been further reported in 14 additional individuals, including in a heterozygous state with no second identified variant in a sibling pair affected with arRP, in 11 individuals with arRP where zygosity information is not provided, and in a heterozygous state in an individual with an unidentified retinal disorder (Avila-Fernandez et al. 2010; Booij et al. 2011; Abu-Safieh et al. 2013; van Huet et al. 2015). The p.Arg102Ser variant was absent from 70 controls (Dryja et al. 1999) and is reported at a frequency of 0.00018 in the South Asian population of the Exome Aggregation Consortium. The Arg102 residue is located in the GMP binding domain in exon 1 and is conserved (Dryja et al. 1999). Based on the collective evidence, the p.Arg102Ser variant is classified as likely pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The PDE6A c.304C>A variant is predicted to result in the amino acid substitution p.Arg102Ser. This variant has been reported in the homozygous and compound heterozygous states in many individuals with retinal disease (see for examples: Dryja et al. 1999. PubMed ID: 10393062; Table S1, Holtan et al. 2019. PubMed ID: 31429209; Table S2, Sharon et al. 2019. PubMed ID: 31456290; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret this variant as pathogenic.