Submissions for variant NM_001142800.2(EYS):c.2528G>A (p.Gly843Glu)

gnomAD frequency: 0.00002  dbSNP: rs74419361

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001041783	SCV001205421	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 843 of the EYS protein (p.Gly843Glu). This variant is present in population databases (rs74419361, gnomAD 0.04%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 22302105, 22363543, 29785639, 31814702; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636026). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000787592	SCV001327051	uncertain significance	Retinitis pigmentosa	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376444	SCV001573585	uncertain significance	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.2528G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV001376444	SCV002022257	pathogenic	Retinitis pigmentosa 25	2021-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001041783	SCV003935685	pathogenic	not provided	2023-06-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22302105, 29785639, 33691693, 34721897, 31253780, 31054281, 31814702, 33946315, 30718709, 33247286, 32218477, 22363543, 32079136, 36284460, 35109811, 33514863)
Baylor Genetics	RCV001376444	SCV004192858	pathogenic	Retinitis pigmentosa 25	2023-10-28	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003889981	SCV004707555	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000787592	SCV004803251	pathogenic	Retinitis pigmentosa	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: EYS c.2528G>A (p.Gly843Glu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 1551158 control chromosomes, predominantly at a frequency of 0.0093 within the East Asian subpopulation in the gnomAD database (v4), including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. However, c.2528G>A has been reported in the literature as a biallelic genotype in many individuals affected with Retinitis Pigmentosa, including multiple cases where it has been found in trans with a pathogenic variant, and it has been found to segregate with disease in multiple families (e.g. Nishiguchi_2021). These data indicate that the variant is very likely to be associated with disease. Additionally, a study evaluating the variant effect using a knockdown zebrafish model found that the variant failed to rescue the phenotype of rhodopsin mislocalization, unlike the WT protein, consistent with the variant resulting in impaired protein function (e.g. Nishiguchi_2021). The following publication has been ascertained in the context of this evaluation (PMID: 33514863). ClinVar contains an entry for this variant (Variation ID: 636026). Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787592	SCV000926573	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001376444	SCV002084453	pathogenic	Retinitis pigmentosa 25	2021-02-11	no assertion criteria provided	clinical testing