Description
Variant summary: EYS c.8648_8655delCATGCAGA (p.Thr2883LysfsX4) is located in the last exon, and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a part of the 3144 amino acids long protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00075 in 157422 control chromosomes, predominantly at a frequency of 0.0064 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency in the Finnish subpopulation is higher than the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.0034). However, the Finnish subpopulation has been recently reported to be enriched for certain founder mutations in EYS (Avela_2018, Avela_2019). The presence of homozygotes in controls suggests that this variant may have incomplete penetrance and/or is associated with a later onset of disease. The variant, c.8648_8655delCATGCAGA, has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa (e.g. Littink_2010, Westin_2021), and was also reported in cis with the c.1155T>A (p.Cys385X) variant in multiple Finish patients (Avela_2018, Avela_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 7) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
