Submissions for variant NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln)

gnomAD frequency: 0.00032  dbSNP: rs28937873

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171240	SCV000221437	likely pathogenic	not provided		criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000393548	SCV000393797	pathogenic	NR2E3-related disorder	2017-09-08	criteria provided, single submitter	clinical testing	The NR2E3 c.932G>A (p.Arg311Gln) variant has been reported in three studies in which it is found in a homozygous state in a total of 12 patients including one unrelated individual, two siblings, and nine related individuals from a single family, all with either enhanced S-cone syndrome (ESCS) or autosomal recessive retinitis pigmentosa (arRP) (Gerber et al. 2000; Chavala et al. 2005; Bernal et al. 2008). In addition, Haider et al. (2000) identified the p.Arg311Gln variant in 13 of 29 unrelated patients with ESCS, however zygosity of the variant was not given. The p.Arg311Gln variant was reported to segregate with disease in multiple families, including a large multi-generation consanguineous family with arRP (Gerber et al. 2000). The p.Arg311Gln variant was absent from 752 controls and is reported at a frequency of 0.00576 in the American population of the 1000 Genomes Project. Gerber et al. (2000) expressed the p.Arg311Gln variant protein in HEK293T cells and found that it hinders the formation of stable dimers but did not significantly alter the in vitro DNA binding capacities or the ability of the protein to repress transcription. Based on the collective evidence, the p.Arg311Gln variant is classified as pathogenic for NR2E3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000171240	SCV000618198	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	Identified in the heterozygous state with no additional NR2E3 variants in patients with enhanced S-cone syndrome, however, the R311Q variant has also been identified in the heterozygous state in unaffected individuals (Milam et al., 2002; Escher et al. 2009); Published functional studies demonstrate mislocalization of the expressed protein to the cytoplasm, reduced DNA binding, and decreased transcriptional activity (Kanda et al., 2009; Escher et al., 2009).; This variant is associated with the following publications: (PMID: 18294254, 17438525, 28944237, 19823680, 25703721, 10655056, 25097241, 19898638, 15689355, 19006237, 28300834, 28541266, 11773633, 11071390)
Counsyl	RCV000668086	SCV000792632	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2017-07-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000668086	SCV000894055	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2022-03-03	criteria provided, single submitter	clinical testing
Invitae	RCV000171240	SCV000935246	pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 311 of the NR2E3 protein (p.Arg311Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs28937873, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with NR2E3-related disorders, including enhanced S cone syndrome, autosomal recessive retinitis pigmentosa, Goldmann-Favre syndrome, and retinal dystrophy (PMID: 10655056, 11071390, 11773633, 16024868, 18294254, 19898638, 26894784). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5532). 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 not expected to disrupt NR2E3 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NR2E3 function (PMID: 11071390, 19006237, 19823680, 19898638, 25703721). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000005870	SCV000966899	pathogenic	Goldmann-Favre syndrome	2018-06-18	criteria provided, single submitter	clinical testing	The p.Arg311Gln variant in NR2E3 has been reported in the homozygous or compound heterozygous state in more than 15 individuals with Enhanced S-cone syndrome an d segregated in >10 affected relatives (Haider 2000, Chavala 2005, Iannaccone 20 09, Lingao 2016, Neuhaus 2017, Patel 2016, Gerber 2000, Bernal 2008, Pachydaki 2 009, Bandah 2009, Habibi 2016). This variant has also been reported in ClinVar ( Variation ID: 5532). This variant has been identified in 0.49% (47/9608) of Ashk enazi Jewish chromosomes, including 1 homozygous individual, by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28937873). Al though this variant has been seen in the general Ashkenazi Jewish population, it s frequency is low enough to be consistent with a recessive carrier frequency. I n vitro functional studies on p.Arg311Gln provide evidence of varying impacts on protein function, potentially resulting in abnormal binding or cellular localiz ation (Escher 2009, Roduit 2009, Kanda 2009, Fradot 2007); however, these studie s types of assays may not accurately represent biological function. Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, the p.Arg311Gln variant is class ified as pathogenic in an autosomal recessive manner for Enhanced S-cone syndrom e. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PS3_Supporting.
Myriad Genetics, Inc.	RCV000005869	SCV001194118	pathogenic	Enhanced S-cone syndrome	2020-01-03	criteria provided, single submitter	clinical testing	NM_014249.2(NR2E3):c.932G>A(R311Q) is classified as pathogenic in the context of NR2E3-related disorders. Sources cited for classification include the following: PMID 10655056, 11071390, 11773633, 18294254, 19006237, 19898638, 24069298, 15689355 and 17438525. Classification of NM_014249.2(NR2E3):c.932G>A(R311Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics	RCV001074891	SCV001240495	pathogenic	Retinal dystrophy	2019-08-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171240	SCV001247332	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095701	SCV001251516	pathogenic	Enhanced S-cone syndrome; NR2E3-related disorder		criteria provided, single submitter	research	The c.932G>A (p.R311Q) missense variant has been observed in the homozygous state and compound heterozygous state in individuals with enhanced S-cone syndrome (PMID: 10655056; 11071390; 11773633; 12963616; 16024868; 18294254; 18436841).
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001374877	SCV001572153	pathogenic	Retinitis pigmentosa 37	2021-04-08	criteria provided, single submitter	research	The NR2E3 c.932G>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: PP1, PS3, PM2, PM3-S . Based on this evidence we have classified this variant as Pathogenic.
Hadassah Hebrew University Medical Center	RCV000005869	SCV001572879	pathogenic	Enhanced S-cone syndrome	2019-06-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000171240	SCV002018367	pathogenic	not provided	2022-08-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000005869	SCV004191586	pathogenic	Enhanced S-cone syndrome	2024-03-28	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000005869	SCV004800994	uncertain significance	Enhanced S-cone syndrome	2024-02-11	criteria provided, single submitter	research
OMIM	RCV000005869	SCV000026051	pathogenic	Enhanced S-cone syndrome	2008-04-01	no assertion criteria provided	literature only
OMIM	RCV000005870	SCV000026052	pathogenic	Goldmann-Favre syndrome	2008-04-01	no assertion criteria provided	literature only
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000005869	SCV000891646	likely pathogenic	Enhanced S-cone syndrome	2017-12-30	no assertion criteria provided	curation
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787633	SCV000926618	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000005869	SCV001161159	pathogenic	Enhanced S-cone syndrome	2019-06-23	no assertion criteria provided	research
Faculty of Health Sciences, Beirut Arab University	RCV001257807	SCV001434685	pathogenic	Autosomal recessive retinitis pigmentosa	2018-09-03	no assertion criteria provided	literature only
Natera, Inc.	RCV000005870	SCV001460513	pathogenic	Goldmann-Favre syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000171240	SCV001551078	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The NR2E3 p.Arg311Gln variant was identified in multiple individuals and families with Enhanced S Cone Syndrome (ESCS), Goldmann-Favre syndrome and retinal dystrophy (Escher_2009_PMID:19006237; Chavala_2005_PMID:16024868; Habibi_2016_PMID:27874104; Zerbib_2019_PMID:28541266; Milam_2001_PMID:P11773633; Wright_2004_PMID:15459973). The variant was identified in dbSNP (ID: rs28937873) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, Invitae and five other laboratories, and as likely pathogenic by Developmental Genetics Unit, King Faisal Specialist Hospital & Research Centre, Department of Genetics, Sultan Qaboos University Hospital, Oman and Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 94 of 230880 chromosomes (1 homozygous) at a frequency of 0.0004071 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 46 of 9790 chromosomes (freq: 0.004699), Other in 5 of 5986 chromosomes (freq: 0.000835), Latino in 22 of 33104 chromosomes (freq: 0.000665), European (non-Finnish) in 18 of 105900 chromosomes (freq: 0.00017), East Asian in 2 of 17158 chromosomes (freq: 0.000117) and African in 1 of 15532 chromosomes (freq: 0.000064), but was not observed in the European (Finnish), or South Asian populations. The p.Arg311 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. Functional studies show some evidence of this variant impacting protein function. This variant is suspected to impair corepressor-binding in ESCS, reduce repression of cone promoters, hinder the ability of photoreceptor cell-specific nuclear receptor (PNR) to form stable dimers, mislocalize in the cytoplasm, have reduced binding and interactions compared to wild type proteins and demonstrates a variable reduction in NR2E3-mediated increase in transcriptional activity (Kanda_2009_PMID:19898638; Gerber_2000_PMID:11071390, Escher_2009_PMID:19006237). However, there is some evidence that the p.R311Q protein behaves similarly to the wild-type protein and that this variant does not significantly alter the in vitro DNA binding capacities and ability of PNR to repress transcription (Roduit_2009_PMID:19823680; Gerber_2000_PMID:11071390). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.