ClinVar Genomic variation as it relates to human health
NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(8); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln)
Variation ID: 5530 Accession: VCV000005530.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 71811591 (GRCh38) [ NCBI UCSC ] 15: 72103931 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Aug 4, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014249.4:c.227G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055064.1:p.Arg76Gln missense NM_016346.4:c.227G>A NP_057430.1:p.Arg76Gln missense NC_000015.10:g.71811591G>A NC_000015.9:g.72103931G>A NG_009113.2:g.6037G>A Q9Y5X4:p.Arg76Gln - Protein change
- R76Q
- Other names
- -
- Canonical SPDI
- NC_000015.10:71811590:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00024
The Genome Aggregation Database (gnomAD) 0.00029
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00045
1000 Genomes Project 30x 0.00047
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NR2E3 | - | - |
GRCh38 GRCh37 |
757 | 772 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000005867.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2016 | RCV000261496.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 10, 2017 | RCV000668029.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 9, 2019 | RCV001075864.3 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV001045323.37 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 3, 2020 | RCV001449793.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jun 14, 2016)
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criteria provided, single submitter
Method: clinical testing
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NR2E3-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000393760.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The c.227G>A (p.Arg76Gln) variant has been reported in one patient with enhanced S-cone syndrome and in a second patient with retinitis pigmentosa. The zygosity state … (more)
The c.227G>A (p.Arg76Gln) variant has been reported in one patient with enhanced S-cone syndrome and in a second patient with retinitis pigmentosa. The zygosity state of the variant is unknown in both patients (Haider et al. 2000; van Huet et al. 2015). The p.Arg76Gln variant was absent from 500 controls and is reported at a frequency of 0.00064 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated the p.Arg76Gln variant leads to subcellular mislocalization, absent DNA binding activity, and reduction of NR2E3-mediated increase in transcriptional activity (Kanda et al. 2009; Roduit et al. 2009). The evidence for this variant is limited. The p.Arg76Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for NR2E3-related disorders. (less)
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Likely pathogenic
(Jul 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Goldmann-Favre syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653074.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
The p.Arg76Gln variant in NR2E3 has been reported in at least 3 homozygous and 2 compound heterozygous individuals with retinal disorders (Haider 2000 PMID: 10655056, … (more)
The p.Arg76Gln variant in NR2E3 has been reported in at least 3 homozygous and 2 compound heterozygous individuals with retinal disorders (Haider 2000 PMID: 10655056, Schorderet 2009 PMID: 10655056, Li 2017 PMID: 28418496, Stone 2017 PMID: 28559085, Murro 2019 PMID: 30324420). It has also been identified in 0.038% (45/119410) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID: 5530). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide evidence that this variant impacts protein function (Kanda 2009 PMID: 19898638, Roduit 2009 PMID: 19823680); however, these types of assays may not accurately represent biological function. Another variant involving this codon (p.Arg76Trp) has been identified in individuals with retinal disease, suggesting change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Enhanced S-Cone syndrome. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate. (less)
Number of individuals with the variant: 2
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Pathogenic
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018368.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001209164.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 76 of the NR2E3 protein (p.Arg76Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 76 of the NR2E3 protein (p.Arg76Gln). This variant is present in population databases (rs104894493, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 30324420; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5530). 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 have shown that this missense change affects NR2E3 function (PMID: 19823680, 19898638, 27013732). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247329.24
First in ClinVar: May 09, 2020 Last updated: Aug 04, 2024 |
Comment:
NR2E3: PM3:Very Strong, PM2, PM5, PP1:Moderate, PS3:Supporting
Number of individuals with the variant: 3
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Uncertain significance
(Jul 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 37
Enhanced S-cone syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000792572.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Aug 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001241503.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447893.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: female
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Pathogenic
(Mar 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Enhanced S-cone syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366569.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5.
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001813632.2
First in ClinVar: Sep 08, 2021 Last updated: Dec 11, 2022 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19823680, 19898638, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19823680, 19898638, 27013732, 28418496, 10655056, 30324420, 19718767, 34426522, 31980526, 32679203, 32531858, 28559085, 26667666) (less)
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Likely pathogenic
(Feb 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Enhanced S-cone syndrome
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556562.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
PS3
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Enhanced S-cone syndrome
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191582.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 01, 2000)
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no assertion criteria provided
Method: literature only
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ENHANCED S-CONE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026049.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 25, 2017 |
Comment on evidence:
In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified an arg76-to-gln mutation resulting from a G-to-A transition in the NR2E3 … (more)
In a patient with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified an arg76-to-gln mutation resulting from a G-to-A transition in the NR2E3 gene. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925426.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951208.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964451.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy. | Murro V | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2019 | PMID: 30324420 |
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. | Stone EM | Ophthalmology | 2017 | PMID: 28559085 |
Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. | Li L | Investigative ophthalmology & visual science | 2017 | PMID: 28418496 |
Survey of variation in human transcription factors reveals prevalent DNA binding changes. | Barrera LA | Science (New York, N.Y.) | 2016 | PMID: 27013732 |
Presentation of Complex Homozygous Allele in ABCA4 Gene in a Patient with Retinitis Pigmentosa. | Audere M | Case reports in ophthalmological medicine | 2015 | PMID: 26229699 |
The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice. | van Huet RA | Molecular vision | 2015 | PMID: 25999674 |
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. | Glöckle N | European journal of human genetics : EJHG | 2014 | PMID: 23591405 |
A comprehensive analysis of sequence variants and putative disease-causing mutations in photoreceptor-specific nuclear receptor NR2E3. | Kanda A | Molecular vision | 2009 | PMID: 19898638 |
Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX. | Roduit R | PloS one | 2009 | PMID: 19823680 |
NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP). | Schorderet DF | Human mutation | 2009 | PMID: 19718767 |
Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family. | Escher P | Human mutation | 2009 | PMID: 19006237 |
Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa. | Coppieters F | American journal of human genetics | 2007 | PMID: 17564971 |
Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. | Haider NB | Nature genetics | 2000 | PMID: 10655056 |
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Text-mined citations for rs104894493 ...
HelpRecord last updated Aug 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.