Submissions for variant NM_001142800.2(EYS):c.7811G>A (p.Arg2604His)

gnomAD frequency: 0.00007  dbSNP: rs368798160

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000998641	SCV001154807	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075538	SCV001241164	uncertain significance	Retinal dystrophy	2018-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000998641	SCV001411178	likely pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2604 of the EYS protein (p.Arg2604His). This variant is present in population databases (rs368798160, gnomAD 0.01%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 29159838, 32531858, 36819107). ClinVar contains an entry for this variant (Variation ID: 809963). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The histidine 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.Arg2604 amino acid residue in EYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20237254, 26161267, 30543658, 31213501). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
MGZ Medical Genetics Center	RCV001832315	SCV002581369	likely pathogenic	Retinitis pigmentosa 25	2022-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000998641	SCV003925780	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 31074760, 29159838)
Baylor Genetics	RCV001832315	SCV004195211	likely pathogenic	Retinitis pigmentosa 25	2023-08-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075538	SCV005070897	uncertain significance	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587008	SCV005076549	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: EYS c.7811G>A (p.Arg2604His) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 157048 control chromosomes. c.7811G>A has been reported in the literature in at-least three individuals affected with Retinitis Pigmentosa (example, Messchaert_2018, Panneman_2023, Pierrache_2019, Weisschuh_2020). These data indicate that the variant may 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: 29159838, 36819107, 31074760, 32531858). ClinVar contains an entry for this variant (Variation ID: 809963). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Clinical Genetics, Academic Medical Center	RCV000998641	SCV001923769	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000998641	SCV001955111	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001832315	SCV002083509	uncertain significance	Retinitis pigmentosa 25	2020-07-02	no assertion criteria provided	clinical testing