Submissions for variant NM_001142800.2(EYS):c.6714del (p.Ile2239fs)

gnomAD frequency: 0.00003  dbSNP: rs752953889

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000367978	SCV000464407	likely pathogenic	Retinitis pigmentosa	2016-08-28	criteria provided, single submitter	clinical testing	The EYS c.6714delT (p.Ile2239SerfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ile2239SerfsTer17 variant has been reported in a total of four individuals with autosomal recessive retinitis pigmentosa, including two homozygotes and two compound heterozygotes (Collin et al. 2008; Barragan et al. 2010; Katagiri et al. 2014; Ge et al. 2015). The variant was absent from the 1051 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Ile2239 residue is highly conserved. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Ile2239SerfsTer17 variant is classified as likely pathogenic for the autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000667003	SCV000791389	pathogenic	Retinitis pigmentosa 25	2017-05-09	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000667003	SCV000889963	pathogenic	Retinitis pigmentosa 25	2016-05-13	criteria provided, single submitter	clinical testing
Invitae	RCV000804054	SCV000943946	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile2239Serfs*17) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs752953889, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 18976725, 21069908, 26667666, 29550188). This variant is also known as p.Pro2238ProfsX16. ClinVar contains an entry for this variant (Variation ID: 357699). For these reasons, this variant has been classified as Pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000667003	SCV000996543	pathogenic	Retinitis pigmentosa 25	2019-06-03	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074382	SCV001239960	pathogenic	Retinal dystrophy	2019-07-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000804054	SCV001248820	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	EYS: PVS1, PM2, PS4:Moderate
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000804054	SCV001447602	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000667003	SCV001573623	pathogenic	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.6714del 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, PM3_strong. Based on this evidence we have classified this variant as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000367978	SCV001950266	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Ile2239SerfsTer17 variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP5. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
MGZ Medical Genetics Center	RCV000667003	SCV002581368	pathogenic	Retinitis pigmentosa 25	2022-06-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000667003	SCV002793698	pathogenic	Retinitis pigmentosa 25	2021-12-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000367978	SCV002819516	pathogenic	Retinitis pigmentosa	2022-12-13	criteria provided, single submitter	clinical testing	Variant summary: EYS c.6714delT (p.Ile2239SerfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.8e-05 in 157482 control chromosomes (gnomAD). c.6714delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Retinitis Pigmentosa and has been shown to segregate with the disease phenotype in at least one family (e.g. Collin_2008, Barragan_2010, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n= 13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000667003	SCV004192909	pathogenic	Retinitis pigmentosa 25	2023-10-05	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001074382	SCV004707459	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
OMIM	RCV000667003	SCV000020718	pathogenic	Retinitis pigmentosa 25	2008-11-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000667003	SCV000804649	pathogenic	Retinitis pigmentosa 25	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000367978	SCV000926579	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001272875	SCV001455291	pathogenic	Autosomal recessive retinitis pigmentosa	2020-09-16	no assertion criteria provided	clinical testing