ClinVar Genomic variation as it relates to human health

Variant summary: EYS c.8805C>A (p.Tyr2935X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Retinosa Pigmentosa in HGMD. The variant allele was found at a frequency of 3.2e-05 in 156836 control chromosomes. c.8805C>A has been reported in the literature as a homozygous and heterozygous genotype in multiple individuals affected with Retinitis Pigmentosa (Example: Koyanagi_2019 and Oishi_2014 etc.). 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. 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Tyr2935*) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 210 amino acid(s) of the EYS protein. This variant is present in population databases (rs527236067, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 22302105, 22363543, 24652164, 25324289, 26161267). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Japanese ancestry (PMID: 22302105, 22363543, 24652164, 25324289, 26161267). This variant is also known as c.8868C>A (p.Y2956X). ClinVar contains an entry for this variant (Variation ID: 143115). For these reasons, this variant has been classified as Pathogenic.

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000143115, PMID:22363543).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000037, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Converted during submission to Pathogenic.

The EYS c.8805C>A variant is predicted to result in premature protein termination (p.Tyr2935*). This variant can also be described as c.8868C>A (p.Tyr2956*) using transcript NM_001292009. This variant has been reported many times in an individual with autosomal recessive retinitis pigmentosa (see for examples Hosono et al. 2012. PubMed ID: 22363543 Katagiri et al. 2014. PubMed ID: 24652164; Dan et al. 2020. PubMed ID: 31960602). This variant is reported in 0.056% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in EYS are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic.