Submissions for variant NM_001142800.2(EYS):c.6416G>A (p.Cys2139Tyr)

gnomAD frequency: 0.00007  dbSNP: rs749909863

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177524	SCV000229407	pathogenic	not provided	2016-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000177524	SCV000948230	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2139 of the EYS protein (p.Cys2139Tyr). This variant is present in population databases (rs749909863, gnomAD 0.2%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 20333770, 25356976, 25753737). 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: 189230). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EYS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075403	SCV001241025	pathogenic	Retinal dystrophy	2018-07-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000177524	SCV001248822	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000177524	SCV001446977	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376308	SCV001573403	likely pathogenic	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.6416G>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: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723741	SCV001950257	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Cys2139Tyr 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: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV001376308	SCV002024540	likely pathogenic	Retinitis pigmentosa 25	2022-12-14	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001376308	SCV002521640	pathogenic	Retinitis pigmentosa 25	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.41). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189230). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20237254) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:20237254). A different missense change at the same codon (p.Cys2139Arg) has been reported to be associated with EYS related disorder (ClinVar ID: VCV001066550 / PMID: 25366773). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV001376308	SCV002580690	likely pathogenic	Retinitis pigmentosa 25	2022-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376308	SCV004192862	pathogenic	Retinitis pigmentosa 25	2024-03-30	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001075403	SCV004707470	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075403	SCV005070086	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001723741	SCV005202439	pathogenic	Retinitis pigmentosa	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: EYS c.6416G>A (p.Cys2139Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 152386 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00014 vs 0.0034), allowing no conclusion about variant significance. c.6416G>A has been reported in the literature as compound heterozygous or homozygous genotype in multiple individuals affected with autosomal ecessive Retinitis Pigmentosa (Rudo_2010, Chen_2015, Gu_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 20333770, 25753737, 27375351). ClinVar contains an entry for this variant (Variation ID: 189230). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001376308	SCV005673265	pathogenic	Retinitis pigmentosa 25	2024-04-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169660	SCV000221188	uncertain significance	not specified	2014-07-15	flagged submission	clinical testing	The Cys2139Tyr variant in EYS has been reported in 3 compound heterozygous and 1 heterozygous individuals with retinitis pigmentosa and was found to segregate with disease in 3 compound heterozygous family members (Audo 2010, Abd El-Aziz 2010, Jin 2014). This variant was not identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) don't provide strong support for or against and impact to the protein and one mammal carries a tyrosine (Tyr) at this position. In summary, while segregation studies and the presence of this variant in combination with other reported pathogenic variants indicate this variant may be disease-causing, the presence of the variant amino acid in a mammal raises some concern and additional studies are required to fully establish its clinical significance.
PreventionGenetics, part of Exact Sciences	RCV003895170	SCV004725292	pathogenic	EYS-related disorder	2023-11-28	no assertion criteria provided	clinical testing	The EYS c.6416G>A variant is predicted to result in the amino acid substitution p.Cys2139Tyr. This variant, in either the compound heterozygous or homozygous states, has been reported in patients with inherited retinal disorders (Supplemental Table S5, Huang et al. 2015. PubMed ID: 25356976; Chen et al. 2015. PubMed ID: 25753737; Audo et al. 2010. PubMed ID: 20333770). This variant is reported in 0.18% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as pathogenic.