Submissions for variant NM_001142800.2(EYS):c.6562A>G (p.Ile2188Val)

gnomAD frequency: 0.00003  dbSNP: rs184448644

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667276	SCV000791698	uncertain significance	Retinitis pigmentosa 25	2017-05-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055122	SCV001219492	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2188 of the EYS protein (p.Ile2188Val). This variant is present in population databases (rs184448644, gnomAD 0.09%). This missense change has been observed in individuals with EYS-related conditions (PMID: 24938718; Invitae). ClinVar contains an entry for this variant (Variation ID: 552077). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Ile2188 amino acid residue in EYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000667276	SCV004195848	uncertain significance	Retinitis pigmentosa 25	2022-02-28	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003889948	SCV004707464	likely benign	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702283	SCV005202806	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: EYS c.6562A>G (p.Ile2188Val) results in a conservative amino acid change located in the Lamnin G domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 149382 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (9.4e-05 vs 0.0034), allowing no conclusion about variant significance. c.6562A>G has been reported in the literature in at-least one individual affected with Retinitis Pigmentosa (Xu_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24938718). ClinVar contains an entry for this variant (Variation ID: 552077). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001272973	SCV001455487	uncertain significance	Retinitis pigmentosa	2020-01-11	no assertion criteria provided	clinical testing