Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 235/10563=2.23%

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

The p.Arg282Trp variant in RP2 has been identified in a Yugoslavian individual with retinitis pigmentosa (PMID: 11462235), but has also been identified in >2% of European (non-Finnish) chromosomes, 556 hemizygotes, and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for X-linked recessive retinitis pigmentosa.

Variant summary: RP2 c.844C>T (p.Arg282Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.018 in 182850 control chromosomes, predominantly at a frequency of 0.03 within the Non-Finnish European subpopulation in the gnomAD database, including 25 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13.86 fold of the estimated maximal expected allele frequency for a pathogenic variant in RP2 causing Retinitis Pigmentosa, X-Linked phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 24265693, 11462235, 22995991, 25097241, 21738648, 27884173, 27535533, 10937588, 22334370, 11992260, 10862093)