Submissions for variant NM_001142800.2(EYS):c.4891C>T (p.Pro1631Ser)

gnomAD frequency: 0.00083  dbSNP: rs200935518

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669700	SCV000794477	uncertain significance	Retinitis pigmentosa 25	2017-09-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000669700	SCV000895774	uncertain significance	Retinitis pigmentosa 25	2021-08-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001164683	SCV001326824	uncertain significance	Retinitis pigmentosa	2018-02-13	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001240732	SCV001413701	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1631 of the EYS protein (p.Pro1631Ser). This variant is present in population databases (rs200935518, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinal disease (PMID: 23591405, 25366773). ClinVar contains an entry for this variant (Variation ID: 554129). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Pars Genome Lab	RCV000669700	SCV001736796	uncertain significance	Retinitis pigmentosa 25	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488794	SCV004242013	uncertain significance	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: EYS c.4891C>T (p.Pro1631Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 153362 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00084 vs 0.0034), allowing no conclusion about variant significance. c.4891C>T has been reported in the literature in individuals affected with Retinitis Pigmentosa (Neveling_2012, Glckle_2013, Messchaert_2018, Colombo_2021, Karali_2022). 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 publications have been ascertained in the context of this evaluation (PMID: 33576794, 23591405, 36460718, 29159838, 22334370). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001240732	SCV001957181	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001240732	SCV001969786	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000669700	SCV002084368	uncertain significance	Retinitis pigmentosa 25	2020-07-22	no assertion criteria provided	clinical testing