Submissions for variant NM_001142800.2(EYS):c.7228+1G>A

gnomAD frequency: 0.00003  dbSNP: rs758899480

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000815788	SCV000956260	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 36 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 (rs758899480, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 27375351). ClinVar contains an entry for this variant (Variation ID: 658881). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001271841	SCV001519435	pathogenic	Retinitis pigmentosa	2021-03-09	criteria provided, single submitter	clinical testing	Variant summary: EYS c.7228+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 that the variant abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 112460 control chromosomes. c.7228+1G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (e.g. Xu_2014, Gu_2016, Messchaert_2018, Wang_2019). 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. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376457	SCV001573605	pathogenic	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.7228+1G>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: PVS1, PM2, PS1. Based on this evidence we have classified this variant as Pathogenic.
MGZ Medical Genetics Center	RCV001376457	SCV002580691	pathogenic	Retinitis pigmentosa 25	2022-04-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001376457	SCV003823944	pathogenic	Retinitis pigmentosa 25	2022-11-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376457	SCV004195242	pathogenic	Retinitis pigmentosa 25	2023-07-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271841	SCV001453311	pathogenic	Retinitis pigmentosa	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000815788	SCV001921613	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000815788	SCV001957109	pathogenic	not provided		no assertion criteria provided	clinical testing