ClinVar Genomic variation as it relates to human health
NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)
Variation ID: 5533 Accession: VCV000005533.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 71811530 (GRCh38) [ NCBI UCSC ] 15: 72103870 (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 Apr 4, 2013 Jul 23, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_014249.4:c.166G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_055064.1:p.Gly56Arg missense NM_016346.4:c.166G>A NP_057430.1:p.Gly56Arg missense NC_000015.10:g.71811530G>A NC_000015.9:g.72103870G>A NG_009113.2:g.5976G>A Q9Y5X4:p.Gly56Arg - Protein change
- G56R
- Other names
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- Canonical SPDI
- NC_000015.10:71811529: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
759 | 774 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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May 30, 2022 | RCV000005871.9 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2018 | RCV000787628.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV001075751.4 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 13, 2023 | RCV000286602.15 |
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
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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
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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
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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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Pathogenic
(May 18, 2015)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000227426.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jun 05, 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: SCV001241381.1
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: SCV001447300.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Rod-cone dystrophy (present)
Sex: female
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Dept Of Ophthalmology, Nagoya University
Accession: SCV004707823.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
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Likely pathogenic
(Feb 05, 2013)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 37
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255426.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 10-19 years
Sex: male
Ethnicity/Population group: Hispanic (Mexico)
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(May 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 37
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002526723.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
Comment:
_x000D_ Criteria applied: PS1, PS4, PP1_STR, PS3_MOD, PM2_SUP
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Pathogenic
(Nov 13, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001205035.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine with arginine at codon 56 of the NR2E3 protein (p.Gly56Arg). The glycine residue is highly conserved and there is a … (more)
This sequence change replaces glycine with arginine at codon 56 of the NR2E3 protein (p.Gly56Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant retinitis pigmentosa (PMID: 17564971, 17982421, 19006237, 26910043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5533). 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: 19006237, 19823680). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 04, 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: SCV000330651.7
First in ClinVar: Dec 06, 2016 Last updated: Jul 23, 2024 |
Comment:
Published functional studies demonstrate a damaging effect (impact on DNA binding and dimerization of transcription factor NR2E3) (PMID: 19823680, 27013732); Not observed at significant frequency … (more)
Published functional studies demonstrate a damaging effect (impact on DNA binding and dimerization of transcription factor NR2E3) (PMID: 19823680, 27013732); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19006237, 26910043, 22661467, 17982421, 32037395, 19898638, 27013732, 32531858, 29034877, 33576794, 30718709, 25326637, 33807610, 31054281, 24938718, 17564971, 19823680) (less)
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Pathogenic
(Jul 01, 2007)
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no assertion criteria provided
Method: literature only
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RETINITIS PIGMENTOSA 37
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026053.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 3 families, 2 Belgian, 1 French, Coppieters et al. (2007) found that autosomal dominant retinitis pigmentosa (RP37; 611131) resulted from a 166G-A transition in … (more)
In 3 families, 2 Belgian, 1 French, Coppieters et al. (2007) found that autosomal dominant retinitis pigmentosa (RP37; 611131) resulted from a 166G-A transition in exon 2 of the NR2E3 gene that caused a gly56-to-arg (G56R) amino acid substitution. (less)
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926613.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
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Pathogenic
(May 02, 2022)
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no assertion criteria provided
Method: clinical testing
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Retinitis pigmentosa 37
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002583439.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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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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Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
Dominant Retinitis Pigmentosa, p.Gly56Arg Mutation in NR2E3: Phenotype in a Large Cohort of 24 Cases. | Blanco-Kelly F | PloS one | 2016 | PMID: 26910043 |
Mutations in the DNA-binding domain of NR2E3 affect in vivo dimerization and interaction with CRX. | Roduit R | PloS one | 2009 | PMID: 19823680 |
Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family. | Escher P | Human mutation | 2009 | PMID: 19006237 |
The Gly56Arg mutation in NR2E3 accounts for 1-2% of autosomal dominant retinitis pigmentosa. | Gire AI | Molecular vision | 2007 | PMID: 17982421 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NR2E3 | - | - | - | - |
Text-mined citations for rs121912631 ...
HelpRecord last updated Nov 03, 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.