ClinVar Genomic variation as it relates to human health

Variant summary: EYS c.2137+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00074 in 156184 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00074 vs 0.0034). The variant, c.2137+1G>A, has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with Retinitis Pigmentosa (example McGuigan_2017, Jespersgaard_2019, Sharon_2020, Colombo_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. There have been 13 assessments for this variant submitted to ClinVar after 2014. Five classified the variant as pathogenic, seven as likely pathogenic, and one as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs199740930, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with retinitis pigmentosa (PMID: 28704921, 30718709, 33576794). ClinVar contains an entry for this variant (Variation ID: 421249). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Observed with a second EYS variant, phase unknown, in patients with retinitis pigmentosa in literature; however, these patients had variants in other genes that may have also contributed to the phenotype (PMID: 32728228, 33576794, 30718709); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30718709, 28704921, 34426522, 31589614, 31456290, 31980526, 32552793, 33576794, 32728228)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 25 (MIM#602772). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 123 heterozygotes, 1 homozygote). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple retinitis pigmentosa individuals, including homozygotes, and is classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar (PMIDs: 28704921, 32728228). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

NG_023443.2(NM_001142800.1):c.2137+1G>A in the EYS gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed as homozygous in an individual affected with retinitis pigmentosa (PMID: 28704921). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3_Supporting; PP4.

The EYS c.2137+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous state or with a second potentially causative variant in several individuals with suspected retinitis pigmentosa (McGuigan et al. 2017. PubMed ID: 28704921; Cundy et al. 2020. PubMed ID: 32728228; Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygous individual. Variants that disrupt the consensus splice donor site in EYS are expected to be pathogenic. In ClinVar, this variant has been interpreted as likely pathogenic or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/421249/). We classify this variant as likely pathogenic.

We have identified this variant in >10 individuals with a retinal dystrophy clinical indication. The variant was only seen in the heterozygous state in these individuals. Further, nearly half had a LP/P variant in another gene which explained their phenotype.