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

gnomAD frequency: 0.00038  dbSNP: rs2723341

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171236	SCV000221433	likely pathogenic	not provided		criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000261643	SCV000393757	pathogenic	NR2E3-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000171236	SCV000565331	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Canonical splice site variant 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, 28224992, 32552793, 32581362, 10655056, 18294254, 19718767, 25097241, 24474277, 15459973, 19273793, 21217109, 21364904, 26894784, 27573156, 29193891, 28771251, 29431110, 30324420, 28559085, 21686439, 31306293, 31130284, 31456290, 31980526, 30959774, 34426522, 33138239, 31589614, 32679203, 32037395, 23591405)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507553	SCV000604567	pathogenic	not specified	2017-05-05	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626919	SCV000747622	pathogenic	Visual impairment; Retinal dystrophy; Color vision defect; Horizontal nystagmus	2017-01-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000171236	SCV000860710	pathogenic	not provided	2018-04-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000668212	SCV000894054	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2022-05-13	criteria provided, single submitter	clinical testing
Invitae	RCV000171236	SCV000951951	pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000005864	SCV001139647	pathogenic	Enhanced S-cone syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000505031	SCV001241471	pathogenic	Retinal dystrophy	2019-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171236	SCV001247328	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	NR2E3: PVS1, PM2, PM3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000005864	SCV001366568	pathogenic	Enhanced S-cone syndrome	2019-03-19	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Hadassah Hebrew University Medical Center	RCV000005864	SCV001572880	pathogenic	Enhanced S-cone syndrome	2019-06-20	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000185571	SCV001573428	likely pathogenic	Retinitis pigmentosa 37	2021-04-08	criteria provided, single submitter	research	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000171236	SCV001762097	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787627	SCV001950299	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	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.
Revvity Omics, Revvity	RCV000171236	SCV002018369	pathogenic	not provided	2021-07-29	criteria provided, single submitter	clinical testing
3billion	RCV000185571	SCV002058364	pathogenic	Retinitis pigmentosa 37	2022-01-03	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000668212	SCV002060378	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37	2021-11-08	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243841	SCV002512538	pathogenic	Ocular albinism	2021-09-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong
Ambry Genetics	RCV002515235	SCV003744735	pathogenic	Inborn genetic diseases	2021-07-16	criteria provided, single submitter	clinical testing	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.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000668212	SCV003930289	pathogenic	Enhanced S-cone syndrome; Retinitis pigmentosa 37		criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000787627	SCV004030428	pathogenic	Retinitis pigmentosa	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Baylor Genetics	RCV000005864	SCV004191580	pathogenic	Enhanced S-cone syndrome	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000005864	SCV000026046	pathogenic	Enhanced S-cone syndrome	2008-04-01	no assertion criteria provided	literature only
OMIM	RCV000185571	SCV000026047	pathogenic	Retinitis pigmentosa 37	2008-04-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185571	SCV000238470	pathogenic	Retinitis pigmentosa 37	2015-06-10	no assertion criteria provided	research	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).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505031	SCV000599197	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678584	SCV000804666	pathogenic	Cone-rod dystrophy	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787627	SCV000926612	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000005864	SCV001161154	pathogenic	Enhanced S-cone syndrome	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001275369	SCV001460499	pathogenic	Goldmann-Favre syndrome	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000171236	SCV001920556	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171236	SCV001955205	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171236	SCV001968097	pathogenic	not provided		no assertion criteria provided	clinical testing