ClinVar Genomic variation as it relates to human health

The PDE6B c.299G>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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.

The p.Arg100His variant in PDE6B was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.

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. 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 PDE6B protein function. ClinVar contains an entry for this variant (Variation ID: 193073). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 22334370, 25472526, 26667666, 28981474, 30998820, 32531858). This variant is present in population databases (rs555600300, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 100 of the PDE6B protein (p.Arg100His).

The PDE6B c.299G>A (p.Arg100His) missense variant has been reported in a presumed compound heterozygous state in three individuals with retinitis pigmentosa (Neveling et al. 2012; Ge et al. 2015; Zhao et al. 2015). Control data are not available for this variant which is reported at a frequency of 0.000170 in the European (non-Finnish) population in the Exome Aggregation Consortium. The evidence for this variant is limited. Therefore, the p.Arg100His variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The p.Arg100His variant in PDE6B has been reported in 2 individuals with isolate d Retinitis pigmentosa. Both patients were compound heterozygous with a second p athogenic allele (Neveling 2012, Ge 2015). It has also been identified in 0.017% (5/29388) of European chromosomes by the Exome Aggregation Consortium (http://e xac.broadinstitute.org/; dbSNP rs555600300). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are require d to fully establish its clinical significance, this variant is likely pathogeni c.

The PDE6B c.299G>A variant is predicted to result in the amino acid substitution p.Arg100His. This variant has been reported in the compound heterozygous state (with either a protein-truncating or canonical splice site variant) and the homozygous state in individuals with retinitis pigmentosa (Neveling et al. 2012. PubMed ID: 22334370; Ge et al. 2015. PubMed ID: 26667666; Comander et al. 2017. PubMed ID: 28981474; Riera et al. 2017. PubMed ID: 28181551). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-619714-G-A). This variant is interpreted as likely pathogenic.