VCV000191059.76 - ClinVar

NM_014249.4(NR2E3):c.119-2A>C

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.

(35)

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.119-2A>C

Variation ID: 191059 Accession: VCV000191059.76

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 71811481 (GRCh38) [ NCBI UCSC ] 15: 72103821 (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	Jun 2, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014249.4:c.119-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_016346.4:c.119-2A>C		splice acceptor
NC_000015.10:g.71811481A>C
NC_000015.9:g.72103821A>C
NG_009113.2:g.5927A>C

... more HGVS ... less HGVS

Protein change

Other names

NP_055064.1:p.?
IVS1AS, A-C

Canonical SPDI

NC_000015.10:71811480:A:C

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.

0.00020 (C)

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

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

The Genome Aggregation Database (gnomAD) 0.00038

Exome Aggregation Consortium (ExAC) 0.00041

Trans-Omics for Precision Medicine (TOPMed) 0.00047

The Genome Aggregation Database (gnomAD), exomes 0.00053

Links

OMIM: 604485.0001 dbSNP: rs2723341 ClinGen: CA235931 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.
Enhanced S-cone syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 28, 2024	RCV000005864.15
Retinitis pigmentosa 37	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV000185571.9
not provided	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000171236.52
NR2E3-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2017	RCV000261643.8
Retinal dystrophy	Pathogenic (2)	criteria provided, single submitter	Jul 25, 2019	RCV000505031.6
not specified	Pathogenic (1)	criteria provided, single submitter	May 5, 2017	RCV000507553.12
Color vision defect Horizontal nystagmus Retinal dystrophy Visual impairment	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626919.5
Cone-rod dystrophy	Pathogenic (1)	no assertion criteria provided	Sep 1, 2016	RCV000678584.8
Enhanced S-cone syndrome Retinitis pigmentosa 37	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 13, 2022	RCV000668212.12
Retinitis pigmentosa	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 24, 2023	RCV000787627.7
Goldmann-Favre syndrome	Pathogenic (1)	no assertion criteria provided	Sep 16, 2020	RCV001275369.4
Ocular albinism	Pathogenic (1)	criteria provided, single submitter	Sep 9, 2021	RCV002243841.5
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 16, 2021	RCV002515235.5
click to load more click to collapse

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.
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Not provided Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000221433.1 First in ClinVar: Jun 02, 2015 Last updated: Jun 02, 2015	Indication for testing: Vision phenotype
Pathogenic (Jul 25, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241471.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 24, 2024)	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: SCV000951951.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 16199547‚ 15459973‚ 27522502‚ 10655056‚ 24474277‚ 25079116‚ 18294254 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Enhanced S-cone syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004191580.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 05, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604567.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Color vision defect Horizontal nystagmus Retinal dystrophy Visual impairment Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747622.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	NR2E3-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000393757.3 First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 23989059‚ 25703721‚ 18294254‚ 21217109‚ 19718767 Comment: 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 … (more) 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. (less)
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Enhanced S-cone syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139647.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Mar 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Enhanced S-cone syndrome Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366568.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Enhanced S-cone syndrome Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001572880.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 37 Affected status: yes Allele origin: germline	3billion Accession: SCV002058364.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Comment: 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 … (more) 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. (less) Clinical Features: Visual impairment (present) , Abnormal retinal morphology (present)
Pathogenic (Sep 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ocular albinism Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512538.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong Geographic origin: Brazil
Pathogenic (Nov 08, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Enhanced S-cone syndrome Retinitis pigmentosa 37 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060378.2 First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022	Publications: PubMed (2) PubMed: 18294254‚ 15459973 Comment: 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: … (more) 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. (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030428.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PVS1, PM2, PS4, PP5.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: female Geographic origin: Portugal
Pathogenic (Jul 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018369.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 16, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003744735.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 10655056‚ 18294254‚ 30718709‚ 32679203 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 03, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565331.8 First in ClinVar: Jun 02, 2015 Last updated: Sep 16, 2024	Comment: 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; … (more) 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) (less)
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247328.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: NR2E3: PM3:Very Strong, PVS1, PM2, PS3:Supporting Number of individuals with the variant: 10
Pathogenic (Apr 02, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000860710.1 First in ClinVar: May 03, 2018 Last updated: May 03, 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
Likely pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 37 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573428.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (21) PubMed: 25703721‚ 25097241‚ 23591405‚ 23989059‚ 21217109‚ 19718767‚ 19273793‚ 18294254‚ 15459973‚ 10655056‚ 24474277‚ 25079116‚ 26894784‚ 27573156‚ 28224992‚ 29193891‚ 28559085‚ 29343940‚ 28771251‚ 29431110‚ 30324420 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762097.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950299.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (22) PubMed: 34906470‚ 25703721‚ 25097241‚ 23591405‚ 23989059‚ 21217109‚ 19718767‚ 19273793‚ 18294254‚ 15459973‚ 10655056‚ 24474277‚ 25079116‚ 26894784‚ 27573156‚ 28224992‚ 29193891‚ 28559085‚ 29343940‚ 28771251‚ 29431110‚ 30324420 Comment: 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 … (more) 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. (less)
Pathogenic (May 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Enhanced S-cone syndrome Retinitis pigmentosa 37 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894054.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 37 Enhanced S-cone syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV003930289.1 First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023
Pathogenic (Apr 01, 2008)	no assertion criteria provided Method: literature only	ENHANCED S-CONE SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026046.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 10655056‚ 18294254 Comment on evidence: Enhanced S-Cone Syndrome In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a … (more) Enhanced S-Cone Syndrome In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a splice acceptor site mutation, an A-to-C transversion in the splice acceptor site of intron 1 of the NR2E3 gene. Another distantly related affected family member was found to be heterozygous for the mutation, which was also identified in 8 simplex probands with ESCS. The mutation was not found in 500 control individuals. Retinitis Pigmentosa 37 In a brother and sister with retinitis pigmentosa and hypopigmented clumped lesions in the posterior pole of both eyes (RP37; 611131), Bernal et al. (2008) identified homozygosity for the 119-2A-C splice acceptor mutation in intron 1 of the NR2E3 gene. Analysis of the RT-PCR products from the mRNA transcripts generated in transient expression studies showed that the mutation generated an aberrant splicing mechanism. The mutation was not found in 60 blood donor controls. (less)
Pathogenic (Apr 01, 2008)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 37 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026047.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 10655056‚ 18294254 Comment on evidence: Enhanced S-Cone Syndrome In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a … (more) Enhanced S-Cone Syndrome In 3 affected individuals of an extensive kindred with enhanced S-cone syndrome (ESCS; 268100), Haider et al. (2000) identified homozygosity for a splice acceptor site mutation, an A-to-C transversion in the splice acceptor site of intron 1 of the NR2E3 gene. Another distantly related affected family member was found to be heterozygous for the mutation, which was also identified in 8 simplex probands with ESCS. The mutation was not found in 500 control individuals. Retinitis Pigmentosa 37 In a brother and sister with retinitis pigmentosa and hypopigmented clumped lesions in the posterior pole of both eyes (RP37; 611131), Bernal et al. (2008) identified homozygosity for the 119-2A-C splice acceptor mutation in intron 1 of the NR2E3 gene. Analysis of the RT-PCR products from the mRNA transcripts generated in transient expression studies showed that the mutation generated an aberrant splicing mechanism. The mutation was not found in 60 blood donor controls. (less)
Pathogenic (Jun 10, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa 37 Affected status: no Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000238470.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Publications: PubMed (5) PubMed: 23591405‚ 25097241‚ 10655056‚ 19273793‚ 18294254 Comment: 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 … (more) 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). (less)
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinal dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000599197.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 28041643 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Sep 01, 2016)	no assertion criteria provided Method: clinical testing	Cone-rod dystrophy Affected status: yes Allele origin: inherited	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804666.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Number of individuals with the variant: 1
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: SCV000926612.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709 Observation 1: Observation 2:
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Goldmann-Favre syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460499.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955205.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Enhanced S-cone syndrome Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161154.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920556.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968097.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
click to load more click to collapse

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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).

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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Enhanced S-Cone Syndrome: Spectrum of Clinical, Imaging, Electrophysiologic, and Genetic Findings in a Retrospective Case Series of 56 Patients.	de Carvalho ER	Ophthalmology. Retina	2021	PMID: 32679203
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.	Murro V	Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie	2019	PMID: 30324420
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.	Reuter MS	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2018	PMID: 29431110
A novel NR2E3 gene mutation in autosomal recessive retinitis pigmentosa with cystic maculopathy.	Mahajan D	Acta ophthalmologica	2018	PMID: 29193891
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.	Lionel AC	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28771251
A new mutation in enhanced S-cone syndrome.	Termühlen J	Acta ophthalmologica	2018	PMID: 27573156
Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration.	Bryant L	Clinical ophthalmology (Auckland, N.Z.)	2017	PMID: 29343940
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Diagnostic exome sequencing in 266 Dutch patients with visual impairment.	Haer-Wigman L	European journal of human genetics : EJHG	2017	PMID: 28224992
New truncation mutation of the NR2E3 gene in a Japanese patient with enhanced S-cone syndrome.	Kuniyoshi K	Japanese journal of ophthalmology	2016	PMID: 27522502
Macular cystoid spaces in patients with retinal dystrophy.	Lingao MD	Ophthalmic genetics	2016	PMID: 26894784
Differential dimerization of variants linked to enhanced S-cone sensitivity syndrome (ESCS) located in the NR2E3 ligand-binding domain.	von Alpen D	Human mutation	2015	PMID: 25703721
Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa.	Wang J	Investigative ophthalmology & visual science	2014	PMID: 25097241
Clinical and molecular characterization of enhanced S-cone syndrome in children.	Hull S	JAMA ophthalmology	2014	PMID: 25079116
Identification of mutations causing inherited retinal degenerations in the israeli and palestinian populations using homozygosity mapping.	Beryozkin A	Investigative ophthalmology & visual science	2014	PMID: 24474277
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies.	Glöckle N	European journal of human genetics : EJHG	2014	PMID: 23591405
Expanded clinical spectrum of enhanced S-cone syndrome.	Yzer S	JAMA ophthalmology	2013	PMID: 23989059
High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population.	Collin RW	Investigative ophthalmology & visual science	2011	PMID: 21217109
NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).	Schorderet DF	Human mutation	2009	PMID: 19718767
The spectrum of retinal diseases caused by NR2E3 mutations in Israeli and Palestinian patients.	Bandah D	Archives of ophthalmology (Chicago, Ill. : 1960)	2009	PMID: 19273793
Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies.	Bernal S	Clinical genetics	2008	PMID: 18294254
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome.	Wright AF	Human mutation	2004	PMID: 15459973
Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate.	Haider NB	Nature genetics	2000	PMID: 10655056
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NR2E3	-	-	-	-
click to load more click to collapse

Text-mined citations for rs2723341 ...

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.119-2A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2723341 ...