rs28937873

chr15-71813573-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM5 PP3 PP5

The NM_014249.4(NR2E3):c.932G>A(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,613,936 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R311W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: NR2E3 NM_014249.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23 U:1
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_014249.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-71813572-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422071.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-71813573-G-A is Pathogenic according to our data. Variant chr15-71813573-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5532.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=14, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr15-71813573-G-A is described in Lovd as [Pathogenic]. Variant chr15-71813573-G-A is described in Lovd as [Pathogenic]. Variant chr15-71813573-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-71813573-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR2E3	NM_014249.4	c.932G>A	p.Arg311Gln	missense_variant	6/8	ENST00000617575.5
NR2E3	NM_016346.4	c.932G>A	p.Arg311Gln	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR2E3	ENST00000617575.5	c.932G>A	p.Arg311Gln	missense_variant	6/8	1	NM_014249.4	P1
NR2E3	ENST00000621098.1	c.932G>A	p.Arg311Gln	missense_variant	6/7	1
NR2E3	ENST00000621736.4	c.668G>A	p.Arg223Gln	missense_variant	8/10	2

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000395 AC: 88 AN: 222622 Hom.: 1 AF XY: 0.000404 AC XY: 49 AN XY: 121336

Gnomad AFR exome AF: 0.0000723

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00475

Gnomad EAS exome AF: 0.0000598

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.000879

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461598 Hom.: 1 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000908

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74488

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000326 Hom.: 1

Bravo AF: 0.000468

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.000291 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:23 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Enhanced S-cone syndrome Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 03, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Likely pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2023	Identified in the heterozygous state with no additional NR2E3 variants in patients with enhanced S-cone syndrome, however, the R311Q variant has also been identified in the heterozygous state in unaffected individuals (Milam et al., 2002; Escher et al. 2009); Published functional studies demonstrate mislocalization of the expressed protein to the cytoplasm, reduced DNA binding, and decreased transcriptional activity (Kanda et al., 2009; Escher et al., 2009).; This variant is associated with the following publications: (PMID: 18294254, 17438525, 28944237, 19823680, 25703721, 10655056, 25097241, 19898638, 15689355, 19006237, 28300834, 28541266, 11773633, 11071390) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	research	Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	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, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with NR2E3-related disorders, including enhanced S cone syndrome, autosomal recessive retinitis pigmentosa, Goldmann-Favre syndrome, and retinal dystrophy (PMID: 10655056, 11071390, 11773633, 16024868, 18294254, 19898638, 26894784). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5532). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on NR2E3 function (PMID: 11071390, 19006237, 19823680, 19898638, 25703721). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Goldmann-Favre syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 18, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -

NR2E3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 08, 2017

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. -

Autosomal recessive retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 03, 2018

- -

Enhanced S-cone syndrome;CN239387:NR2E3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

-

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). -

Retinitis pigmentosa 37 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

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. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 13, 2019

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Benign	0.82
Eigen	Benign	0.059
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.63	.;P;.
Vest4		0.71
MVP		0.62
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.55
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.69		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs28937873; hg19: chr15-72105913;