Submissions for variant NM_001142800.2(EYS):c.977G>A (p.Ser326Asn)

gnomAD frequency: 0.00379  dbSNP: rs112822256

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513566	SCV000609218	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	EYS: BP4
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625446	SCV000745373	likely benign	Retinitis pigmentosa 25	2017-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000625446	SCV000794865	uncertain significance	Retinitis pigmentosa 25	2017-10-18	criteria provided, single submitter	clinical testing
Invitae	RCV000513566	SCV001118443	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074080	SCV001239649	uncertain significance	Retinal dystrophy	2018-12-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000504943	SCV001319940	uncertain significance	Retinitis pigmentosa	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000513566	SCV001859809	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32581362, 28041643)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001700135	SCV004241059	likely benign	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: EYS c.977G>A (p.Ser326Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) 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 0.0018 in 250760 control chromosomes, predominantly at a frequency of 0.0082 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.977G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa (Audo_2010, Wang_2014, El Shamieh_2015, Dieiro_2020). These reports 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 publications have been ascertained in the context of this evaluation (PMID: 20333770, 32483926, 25692139, 32581362, 25097241). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as likely pathogenic (n=1), uncertain significance (n=5), likely benign (n=3) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003915401	SCV004731749	benign	EYS-related condition	2020-12-16	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504943	SCV000599168	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504943	SCV000926929	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001277019	SCV001463752	uncertain significance	Autosomal recessive retinitis pigmentosa	2020-06-17	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700135	SCV001924471	benign	not specified		no assertion criteria provided	clinical testing