Submissions for variant NM_014249.4(NR2E3):c.925C>G (p.Arg309Gly)

dbSNP: rs774102273

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379522	SCV001577334	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 309 of the NR2E3 protein (p.Arg309Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal recessive enhanced S-cone syndrome (PMID: 10655056, 15459973, 19718767; Invitae). ClinVar contains an entry for this variant (Variation ID: 1068080). 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 NR2E3 protein function. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 24069298, 25703721, 28300834). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001831369	SCV005053701	pathogenic	Enhanced S-cone syndrome	2024-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005057350	SCV005726328	pathogenic	Retinitis pigmentosa	2024-11-14	criteria provided, single submitter	clinical testing	Variant summary: NR2E3 c.925C>G (p.Arg309Gly) results in a non-conservative amino acid change located in the Nuclear receptor (NR) ligand-binding (LBD) domain (IPR000536) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 242578 control chromosomes. c.925C>G has been reported in the literature in compound heterozygous individuals affected with autosomal recessive Enhanced S-cone syndrome (Haider_2000, Wright_2004, daPalma_2022, Schorderet_2009, Galantuomo_2008, Invitae). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in partial mislocalization of the mutant protein to cytoplasm, loss of DNA binding activity and reduced dimerazation and transcription activity of heterodimers (Fradot_2007, Kanda_2009, von Alpen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 17438525, 28300834, No PMID, 10655056, 19898638, 19718767, 15459973, 36067420, 25703721). ClinVar contains an entry for this variant (Variation ID: 1068080). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001831369	SCV002085629	likely pathogenic	Enhanced S-cone syndrome	2020-07-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004531189	SCV004744620	likely pathogenic	NR2E3-related disorder	2023-10-20	no assertion criteria provided	clinical testing	The NR2E3 c.925C>G variant is predicted to result in the amino acid substitution p.Arg309Gly. This variant was reported in at least one individual with autosomal recessive enhanced S-cone syndrome (Haider. 2000. PubMed ID: 10655056; Wright. 2004. PubMed ID: 15459973; Schorderet. 2009. PubMed ID: 19718767) with in vitro experiments finding this variant affects protein function (Kanda. 2009. PubMed ID: 19898638; von Alpen. 2015. PubMed ID: 25703721; Fradot. 2007. PubMed ID: 17438525; Tan. 2013. PubMed ID: 24069298). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-72105906-C-G). This variant is interpreted as likely pathogenic.