rs104894493

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PM1PM5PP5_Very_StrongBP4

The NM_014249.4(NR2E3):c.227G>A(p.Arg76Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00031 in 1,604,280 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

NR2E3
NM_014249.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21U:1

Conservation

PhyloP100: 5.60

Publications

17 publications found

Variant links:

Genes affected

NR2E3 (HGNC:7974): (nuclear receptor subfamily 2 group E member 3) This protein is part of a large family of nuclear receptor transcription factors involved in signaling pathways. Nuclear receptors have been shown to regulate pathways involved in embryonic development, as well as in maintenance of proper cell function in adults. Members of this family are characterized by discrete domains that function in DNA and ligand binding. This gene encodes a retinal nuclear receptor that is a ligand-dependent transcription factor. Defects in this gene are a cause of enhanced S cone syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

NR2E3 Gene-Disease associations (from GenCC):

retinitis pigmentosa 37
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
enhanced S-cone syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Goldmann-Favre syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NR2E3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_014249.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-71811590-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 15-71811591-G-A is Pathogenic according to our data. Variant chr15-71811591-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3437796). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2E3	NM_014249.4 link	c.227G>A	p.Arg76Gln	missense_variant	Exon 2 of 8	ENST00000617575.5	NP_055064.1	Q9Y5X4-1
NR2E3	NM_016346.4 link	c.227G>A	p.Arg76Gln	missense_variant	Exon 2 of 7		NP_057430.1	Q9Y5X4-2F1D8Q9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NR2E3	ENST00000617575.5 link	c.227G>A	p.Arg76Gln	missense_variant	Exon 2 of 8	1	NM_014249.4	ENSP00000482504.1	Q9Y5X4-1
NR2E3	ENST00000621098.1 link	c.227G>A	p.Arg76Gln	missense_variant	Exon 2 of 7	1		ENSP00000479962.1	Q9Y5X4-2
NR2E3	ENST00000621736.4 link	c.-38G>A		5_prime_UTR_variant	Exon 4 of 10	2		ENSP00000479254.1	Q8IVZ9

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000200

AC:

AN:

230318

AF XY:

0.000160

show subpopulations

Gnomad AFR exome

AF:

0.0000741

Gnomad AMR exome

AF:

0.0000927

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000495

Gnomad NFE exome

AF:

0.000337

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000310

AC:

450

AN:

1451962

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

232

AN XY:

721282

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33334

American (AMR)

AF:

0.0000694

AC:

AN:

43208

Ashkenazi Jewish (ASJ)

AF:

0.000193

AC:

AN:

25962

East Asian (EAS)

AF:

0.00

AC:

AN:

39212

South Asian (SAS)

AF:

0.000356

AC:

AN:

84154

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

52362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000348

AC:

386

AN:

1108026

Other (OTH)

AF:

0.000300

AC:

AN:

59990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000309

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000420

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000476

AC:

ExAC

AF:

0.000240

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NR2E3: PM3:Very Strong, PM2, PM5, PP1:Moderate, PS3:Supporting -

Mar 29, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19823680, 19898638, 27013732, 28418496, 10655056, 30324420, 19718767, 34426522, 31980526, 32679203, 32531858, 28559085, 26667666, 37222315, 38317096, 31964843, 37734845, 34321860) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 12, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5530). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Enhanced S-cone syndrome

Pathogenic:4

Feb 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 03, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3 -

Mar 29, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5. -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37

Pathogenic:2Uncertain:1

Apr 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 10, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

NR2E3-related disorder

Pathogenic:2

Sep 05, 2024

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The NR2E3 c.227G>A variant is predicted to result in the amino acid substitution p.Arg76Gln. This variant has been previously reported in individuals with enhanced S-cone syndrome or autosomal recessive retinal disease (see for example Haider et al. 2000. PubMed ID: 10655056; Li et al. 2017. PubMed ID: 28418496; Stone et al. 2017. PubMed ID: 28559085, Supplementary Table 1). An alternate nucleotide change affecting the same amino acid (c.226C>T, p.Arg76Trp) has also been reported in individuals with retinal disease (Haider et al. 2000. PubMed ID: 10655056; Ge et al. 2015. PubMed ID: 26667666; Stone et al. 2017. PubMed ID: 28559085, Supplementary Table 1). This variant is reported in 0.038% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Retinal dystrophy

Pathogenic:2

Aug 09, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 37

Pathogenic:1

Aug 28, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variant was identified, NM_014249.3(NR2E3):c.227G>A in exon 2 of 8 of the NR2E3 gene. This substitution is predicted to create a minor amino acid change from an arginine to glutamine at position 76 of the protein, NP_055064.1(NR2E3):p.(Arg76Gln). The arginine at this position has moderate conservation (100 vertebrates, UCSC). It is located within the NR_DBD_like domain and is a putative DNA binding site. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD). The variant is present in the gnomAD population database at a frequency of 0.02% (56 heterozygotes, 0 homozygotes). An alternative residue change at the same location to a tryptophan has been reported in the gnomAD database at a frequency of 0.003% (9 heterozygote, 0 homozygotes). The variant has been previously reported pathogenic in patients with retinal dystrophy (Li L. et al. (2017); Murro, V. et al. (2019)). In addition, functional studies show that this variant increased NR2E3 dimer formation, decreased NR2E3-CRX interaction, abolished DNA binding and impaired transcriptional activity of NR2E3 (Roduit R. et al. (2009)). A different variant in the same codon resulting in a change to tryptophan has been shown to cause enhanced S-cone syndrome (ClinVar). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -

Goldmann-Favre syndrome

Pathogenic:1

Jul 03, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.3

L;L

PhyloP100

5.6

PrimateAI

Uncertain

0.69

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.86

MVP

0.71

ClinPred

0.45

GERP RS

4.1

Varity_R

0.36

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over