rs2723341

Positions:

• chr15-71811481-A-C
• chr15-71811481-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_014249.4(NR2E3):​c.119-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00066 in 1,555,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: NR2E3 NM_014249.4 splice_acceptor
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35
• Conservation: PhyloP100: 4.05

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 15-71811481-A-C is Pathogenic according to our data. Variant chr15-71811481-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-71811481-A-C is described in Lovd as [Pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Likely_pathogenic]. Variant chr15-71811481-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR2E3	NM_014249.4	c.119-2A>C		splice_acceptor_variant		ENST00000617575.5	NP_055064.1
NR2E3	NM_016346.4	c.119-2A>C		splice_acceptor_variant			NP_057430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR2E3	ENST00000617575.5	c.119-2A>C		splice_acceptor_variant		1	NM_014249.4	ENSP00000482504	P1
NR2E3	ENST00000621098.1	c.119-2A>C		splice_acceptor_variant		1		ENSP00000479962
NR2E3	ENST00000621736.4	c.-146-2A>C		splice_acceptor_variant		2		ENSP00000479254

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000526 AC: 85 AN: 161472 Hom.: 0 AF XY: 0.000511 AC XY: 44 AN XY: 86034

Gnomad AFR exome AF: 0.000367

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000866

Gnomad FIN exome AF: 0.0000618

Gnomad NFE exome AF: 0.000990

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000676 AC: 949 AN: 1402938 Hom.: 0 Cov.: 33 AF XY: 0.000683 AC XY: 473 AN XY: 692406

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000111

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000629

Gnomad4 FIN exome AF: 0.0000404

Gnomad4 NFE exome AF: 0.000791

Gnomad4 OTH exome AF: 0.000688

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74380

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000927

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000615 Hom.: 0

Bravo AF: 0.000468

ExAC AF: 0.000192 AC: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change affects an acceptor splice site in intron 1 of the NR2E3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NR2E3 are known to be pathogenic (PMID: 15459973, 27522502). This variant is present in population databases (rs2723341, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with autosomal recessive enhanced S-cone syndrome (PMID: 10655056, 24474277, 25079116). It has also been observed to segregate with disease in related individuals. This variant is also known as c.118-2A>C. ClinVar contains an entry for this variant (Variation ID: 191059). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18294254). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 02, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NR2E3: PM3:Very Strong, PVS1, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2024	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25079116, 29343940, 32531858, 31725702, 32552793, 32581362, 10655056, 18294254, 19718767, 25097241, 24474277, 19273793, 21364904, 26894784, 27573156, 29193891, 28771251, 29431110, 28559085, 21686439, 31130284, 31980526, 30959774, 34426522, 31589614, 32679203, 32037395, 31816670, 31877679, 35113758, 31306293, 28224992, 30324420, 23591405, 31456290, 33138239, 21217109, 15459973) -

Enhanced S-cone syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 19, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

Retinitis pigmentosa 37 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 10, 2015	The NR2E3 variant (c.119-2A>C) identified in this patient is located in the -2 position of the splice acceptor site of intron 1 and segregated with retinitis pigmentosa in multiple families (Bandah et al. 2009, PMID 19273793; Haider et al. 2000, PMID 10655056; Beryozkin et al 2014, PMID 24474277; Wang et al 2014, PMID 25097241). Additionally, in vivo functional studies demonstrated altered splicing (PMID 18294254; Bernal et al 2008). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000191059, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000503, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The NR2E3 c.119-2A>C 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: PS3, PM2, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Retinitis pigmentosa Pathogenic:3

Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The c.119-2A>C variant in NR2E3 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Enhanced S-cone syndrome;C1970163:Retinitis pigmentosa 37 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_014249.2(NR2E3):c.119-2A>C is a canonical splice variant classified as pathogenic in the context of NR2E3-related disorders. c.119-2A>C has been observed in cases with relevant disease (PMID: 18294254, 15459973). Functional assessments of this variant are available in the literature (PMID: 18294254). c.119-2A>C has been observed in population frequency databases (gnomAD: NFE 0.1%). In summary, NM_014249.2(NR2E3):c.119-2A>C is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Retinal dystrophy Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 25, 2019	- -

NR2E3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The NR2E3 c.119-2A>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.119-2A>C variant has been reported in 56 of 232 patients with NR2E3-related disorders, including 33 homozygotes and 23 compound heterozygotes. The variant is noted to segregate with disease (Schorderet et al. 2009; Collin et al. 2011; Yzer et al. 2013; Von Alpen et al. 2015). This variant was absent from 667 controls and is reported at a frequency of 0.00070 in the European (non-Finnish) population of the Exome Aggregation Consortium. Bernal et al. (2008) demonstrated that the c.119-2A>C variant resulted in aberrant splicing producing, in addition to the normal transcript, a transcript showing skipping of exon 2 and the generation of a premature stop codon in exon 3. Based on the evidence, the c.119-2A>C 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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2021

The c.119-2A>C intronic variant results from a A to C substitution two nucleotides before coding exon 2 of the NR2E3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the NR2E3 c.119-2A>C alteration was observed in 0.05% (97/192,798) of total alleles studied, with a frequency of 0.11% (10/8,884) in the Ashkenazi Jewish subpopulation. This alteration has been reported homozygous or compound heterozygous with a second variant in multiple unrelated patients with retinitis pigmentosa or enhanced S-cone syndrome (Haider, 2000; Bernal, 2008; Jespersgaard, 2019; De Carvalho, 2021). Expression of the c.119-2A>C mutant protein in COS7 cells and RT-PCR showed an abnormal transcript due to exon 2 skipping and the generation of a premature stop codon in exon 3 (Bernal, 2008). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Goldmann-Favre syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 05, 2017

- -

Color vision defect;C0271385:Horizontal nystagmus;C0854723:Retinal dystrophy;C3665347:Visual impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Ocular albinism Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 09, 2021

ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong -

Cone-rod dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Sep 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.76	D
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		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: rs2723341; hg19: chr15-72103821;