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.
ClinVar Genomic variation as it relates to human health
NM_014249.4(NR2E3):c.119-2A>C
Germline
Classification
Help
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)
Help
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
35
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
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 - Protein change
- -
- Other names
-
NP_055064.1:p.?
IVS1AS, A-C
- Canonical SPDI
- NC_000015.10:71811480:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00053
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
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
759 | 774 | |
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. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2024 | RCV000005864.15 | |
| Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000171236.52 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2022 | RCV000185571.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000261643.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 5, 2017 | RCV000507553.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 13, 2022 | RCV000668212.12 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 25, 2019 | RCV000505031.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000626919.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2016 | RCV000678584.8 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000787627.7 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001275369.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 9, 2021 | RCV002243841.5 | |
| 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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 20, 2019)
|
criteria provided, single submitter
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
(Jun 17, 2021)
|
criteria provided, single submitter
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
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
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
(Apr 02, 2018)
|
criteria provided, single submitter
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 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Apr 27, 2017)
|
criteria provided, single submitter
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 |
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
(Jul 25, 2019)
|
criteria provided, single submitter
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
|
|
|
|
Likely pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
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 |
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
(Apr 01, 2021)
|
criteria provided, single submitter
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 |
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
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 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
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
(Jan 24, 2024)
|
criteria provided, single submitter
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 |
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
(Jul 16, 2021)
|
criteria provided, single submitter
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 |
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 28, 2024)
|
criteria provided, single submitter
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
(Mar 03, 2024)
|
criteria provided, single submitter
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
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
(May 05, 2017)
|
criteria provided, single submitter
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
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
(May 28, 2019)
|
criteria provided, single submitter
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
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
(Jan 03, 2022)
|
criteria provided, single submitter
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
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
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 |
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
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.
|
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
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
(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 |
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)
|
|
|
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 |
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 |
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)
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Pathogenic
(Apr 01, 2018)
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no assertion criteria provided
Method: research
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Retinitis pigmentosa
Affected status: yes
Allele origin:
unknown
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Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926612.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023 |
Observation 1: Observation 2: |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Likely pathogenic
(Jan 01, 2015)
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no assertion criteria provided
Method: research
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Retinal dystrophy
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599197.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European
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Pathogenic
(Sep 01, 2016)
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no assertion criteria provided
Method: clinical testing
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Cone-rod dystrophy
Affected status: yes
Allele origin:
inherited
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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
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Enhanced S-cone syndrome
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001161154.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Goldmann-Favre syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460499.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Comment:
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:
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 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:
NR2E3: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
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:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong
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:
Clinical significance based on ACMG v2.0
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:
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:
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:
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 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:
NR2E3: PM3:Very Strong, PVS1, PM2, PS3:Supporting
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
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:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM3 very strong, PP1 strong
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:
Clinical significance based on ACMG v2.0
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).
Citations for germline classification of this variant
Help| 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 | - | - | - | - |
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Text-mined citations for rs2723341 ...
HelpThese 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 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.