Submissions for variant NM_014249.4(NR2E3):c.767C>A (p.Ala256Glu)

dbSNP: rs377257254

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000809974	SCV000950160	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 256 of the NR2E3 protein (p.Ala256Glu). This variant is present in population databases (rs377257254, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive NR2E3-related conditions (PMID: 12963616, 25079116). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438229). 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) performed at Invitae indicates that this missense variant is expected to disrupt NR2E3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NR2E3 function (PMID: 19898638, 25703721, 28300834). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000504973	SCV001240865	pathogenic	Retinal dystrophy	2017-07-05	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376214	SCV001573279	likely pathogenic	Retinitis pigmentosa 37	2021-04-08	criteria provided, single submitter	research	The NR2E3 c.767C>A 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: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449815	SCV001653112	pathogenic	Goldmann-Favre syndrome	2020-06-04	criteria provided, single submitter	clinical testing	The p.Ala256Glu variant in NR2E3 has been reported in the compound heterozygous state 6 individuals with retinal disease (Sharon 2003 PMID:12963616, Hull 2014 PMID:25079116, Carss 2017 PMID: 28041643, Bryant 2018 PMID: 29343940). It has also been identified in 0.009% (3/34014) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID:438229). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Kanda 2009 PMID: 19898638, von Alpen 2015 PMID: 25703721). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Moderate, PP3.
GeneDx	RCV000809974	SCV001824694	likely pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate impairment of protein localization, binding, and function (Kanda et al., 2009; Fulton et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; however, Splice predictors are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31589614, 32679203, 16225923, 24425859, 19718767, 12963616, 15459973, 28041643, 29343940, 15453866, 28300834, 25097241, 25703721, 19898638, 25079116)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001724033	SCV001950300	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Ala256Glu variant in NR2E3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Baylor Genetics	RCV003464084	SCV004191596	pathogenic	Enhanced S-cone syndrome	2023-10-08	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504973	SCV000599200	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research