Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics Laboratory, |
RCV001199689 | SCV001162503 | pathogenic | Central areolar choroidal dystrophy | 2020-01-09 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001229450 | SCV001401895 | likely pathogenic | not provided | 2023-08-04 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 813181). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 32531858; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2410 of the EYS protein (p.Ala2410Ser). This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317412 | SCV004020806 | uncertain significance | not specified | 2023-06-16 | criteria provided, single submitter | clinical testing | Variant summary: EYS c.7228G>T (p.Ala2410Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. In addition, this variant disrupts the last nucleotide of exon 36, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site, and one predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 115132 control chromosomes (gnomAD, v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7228G>T has been reported in the literature in at least one compound heterozygous individual affected with central areolar choroidal dystrophy (e.g., Weisschuh_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 32531858). Three ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: two submitters classified the variant as uncertain significance, and one submitter classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Natera, |
RCV001832325 | SCV002083528 | uncertain significance | Retinitis pigmentosa 25 | 2021-04-27 | no assertion criteria provided | clinical testing |