ClinVar Miner

Submissions for variant NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) (rs28937873)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000171240 SCV000221437 likely pathogenic not provided criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000393548 SCV000393797 pathogenic NR2E3-Related Disorders 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 2018-06-27 criteria provided, single submitter clinical testing The c.932 G>A variant in the NR2E3 gene has been reported previously in association with enhanced S-cone syndrome (ESCS) when present in the heterozygous state, the homozygous state, or when in trans with another disease-causing variant (Milam et al., 2002; Escher et al. 2009). Functional studies have shown the c.932 G>A pathogenic variant results in mislocalization of the expressed protein to the cytoplasm, reduced DNA binding, and transcriptional activity (Kanda et al., 2009; Escher et al., 2009). In-silico splice models predict that c.932 G>A may create a cryptic splice acceptor site downstream of the natural SAS. However, in the absence of RNA/functional studies, the actual effect of the c.932 G>A change in this individual is unknown. If c.932 G>A does not alter splicing, it will result in the R311Q missense change. The R311Q variant is observed in 28/57472 (0.049%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R311Q variant is a semi-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R311Q as a pathogenic variant.
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 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000171240 SCV000935246 pathogenic not provided 2020-10-26 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, ExAC 0.05%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the homozygous or compound-heterozygous state in many families and individuals affected with NR2E3-related disorders, including enhanced S cone syndrome, autosomal recessive retinitis pigmentosa, Goldmann-Favre syndrome, and retinal dystrophy (PMID: 11071390, 16024868, 10655056, 11773633, 19898638, 18294254, 26894784). ClinVar contains an entry for this variant (Variation ID: 5532). Experimental studies do not agree on the effect of this missense change on protein function. Some studies suggest it affects transcriptional activity, localization, homo-dimerization, and co-repressor binding, while others suggest it behaves similar to wild type (PMID: 19823680, 19006237, 19898638, 25703721, 11071390). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000171240 SCV001247332 pathogenic not provided 2019-08-01 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 Disorders 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
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, Oman RCV000005869 SCV000891646 likely pathogenic Enhanced S-cone syndrome 2017-12-30 no assertion criteria provided curation
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, 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.

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