Submissions for variant NM_001142800.2(EYS):c.9392G>C (p.Gly3131Ala)

gnomAD frequency: 0.00006  dbSNP: rs772888249

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000513040	SCV000609211	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001162434	SCV001162508	pathogenic	Retinitis pigmentosa	2020-01-09	criteria provided, single submitter	research
Invitae	RCV000513040	SCV001224408	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 3131 of the EYS protein (p.Gly3131Ala). This variant is present in population databases (rs772888249, gnomAD 0.01%). This missense change has been observed in individual(s) with EYS-related conditions (PMID: 31456290, 32531858, 36764454; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 444685). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. This variant disrupts the p.Gly3131 amino acid residue in EYS. Other variant(s) that disrupt this residue have been observed in individuals with EYS-related conditions (PMID: 33576794), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001162434	SCV001324387	uncertain significance	Retinitis pigmentosa	2018-01-13	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.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376277	SCV001573361	uncertain significance	Retinitis pigmentosa 25	2021-04-08	criteria provided, single submitter	research	The EYS c.9392G>C 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: PM2, PM3-P. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Pars Genome Lab	RCV001376277	SCV001652860	uncertain significance	Retinitis pigmentosa 25	2021-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV002248747	SCV002517034	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001162434	SCV003929183	likely pathogenic	Retinitis pigmentosa	2023-04-06	criteria provided, single submitter	clinical testing	Variant summary: EYS c.9392G>C (p.Gly3131Ala) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-05 in 134594 control chromosomes. c.9392G>C has been reported in the literature in homozygous and compound heterozygous individuals affected with Retinitis Pigmentosa (Sharon_2020, Weisschuh_2020, Soares_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and as pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001376277	SCV004192914	likely pathogenic	Retinitis pigmentosa 25	2023-10-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001271835	SCV001453298	uncertain significance	Autosomal recessive retinitis pigmentosa	2020-09-16	no assertion criteria provided	clinical testing