Submissions for variant NM_001142800.2(EYS):c.8648_8655del (p.Thr2883fs)

dbSNP: rs528919874

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664636	SCV000788634	likely pathogenic	Retinitis pigmentosa 25	2017-12-29	criteria provided, single submitter	clinical testing
Invitae	RCV000802397	SCV000942227	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr2883Lysfs*4) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the EYS protein. This variant is present in population databases (rs528919874, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 20537394). It has also been observed to segregate with disease in related individuals. This variant is also known as c.8710_8717del8 (p.T2904KfsX4). ClinVar contains an entry for this variant (Variation ID: 550019). This variant disrupts a region of the EYS protein in which other variant(s) (p.Tyr2935*) have been determined to be pathogenic (PMID: 22363543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073669	SCV001239221	pathogenic	Retinal dystrophy	2019-08-09	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000664636	SCV001573433	pathogenic	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.8648_8655del 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. Based on this evidence we have classified this variant as Pathogenic.
GeneDx	RCV000802397	SCV001813684	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	Commonly seen in cis with the p.(C385*) variant in individuals of Finish background (Avela et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 262 amino acids are lost and replaced with 3 incorrect amino acids; This variant is associated with the following publications: (PMID: 30718709, 20537394, 29159838, 28704921, 29550188, 31429209, 32531858, 29068140, 33833316)
MGZ Medical Genetics Center	RCV000664636	SCV002579229	likely pathogenic	Retinitis pigmentosa 25	2022-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000787599	SCV003922791	pathogenic	Retinitis pigmentosa	2023-03-24	criteria provided, single submitter	clinical testing	Variant summary: EYS c.8648_8655delCATGCAGA (p.Thr2883LysfsX4) is located in the last exon, and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a part of the 3144 amino acids long protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00075 in 157422 control chromosomes, predominantly at a frequency of 0.0064 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency in the Finnish subpopulation is higher than the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.0034). However, the Finnish subpopulation has been recently reported to be enriched for certain founder mutations in EYS (Avela_2018, Avela_2019). The presence of homozygotes in controls suggests that this variant may have incomplete penetrance and/or is associated with a later onset of disease. The variant, c.8648_8655delCATGCAGA, has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa (e.g. Littink_2010, Westin_2021), and was also reported in cis with the c.1155T>A (p.Cys385X) variant in multiple Finish patients (Avela_2018, Avela_2019). 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. Nine ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 7) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000664636	SCV004192871	pathogenic	Retinitis pigmentosa 25	2024-03-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000664636	SCV004235273	pathogenic	Retinitis pigmentosa 25	2023-06-22	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787599	SCV000926582	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000664636	SCV001142361	pathogenic	Retinitis pigmentosa 25	2020-01-06	no assertion criteria provided	curation	NM_001142800.1:c.8648_8655delCATGCAGA in the EYS gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This sequence change results in a premature translational stop signal in the EYS gene (p.Thr2883Lysfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acids of the EYS protein. This variant has been observed in a patient with retinitis pigmentosa, in a compound heterozygous state with c.4350_4356del7 (p.K1450KfsX3) (PMID: 20537394). This variant is also known as c.8710_8717del8 (p.T2904KfsX4) in the literature. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4.
Natera, Inc.	RCV000664636	SCV002083481	pathogenic	Retinitis pigmentosa 25	2021-08-23	no assertion criteria provided	clinical testing