VCV000005533.19 - ClinVar

NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)

Germline

Classification

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.

(11)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)

Variation ID: 5533 Accession: VCV000005533.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 71811530 (GRCh38) [ NCBI UCSC ] 15: 72103870 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

G56R

Other names

Canonical SPDI

NC_000015.10:71811529:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA253522 UniProtKB: Q9Y5X4#VAR_037026 OMIM: 604485.0006 dbSNP: rs121912631 VarSome

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
Gene	OMIM	HI score Help 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.
NR2E3		-	-	GRCh38 GRCh37	760	775

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.
Retinitis pigmentosa 37	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 30, 2022	RCV000005871.9
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Nov 13, 2023	RCV000286602.15
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787628.1
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001075751.4

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.
Pathogenic (May 18, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227426.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NR2E3 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jun 05, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241381.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal unknown) Affected status: yes Allele origin: germline	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
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004707823.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Likely pathogenic (Feb 05, 2013)	criteria provided, single submitter (Lee et al. (JAMA. 2014)) Method: clinical testing	Retinitis pigmentosa 37 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	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
Pathogenic (May 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 37 Affected status: yes Allele origin: unknown	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
Pathogenic (Nov 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001205035.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 17564971‚ 17982421‚ 19006237‚ 26910043‚ 19823680 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)
Pathogenic (Aug 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	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)
Pathogenic (Jul 01, 2007)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 37 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026053.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 17564971 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)
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926613.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (May 02, 2022)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 37 Affected status: yes Allele origin: germline	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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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 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.

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 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)

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_014249.4(NR2E3):c.166G>A (p.Gly56Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121912631 ...