ClinVar Genomic variation as it relates to human health
NM_000330.4(RS1):c.304C>T (p.Arg102Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000330.4(RS1):c.304C>T (p.Arg102Trp)
Variation ID: 9887 Accession: VCV000009887.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.13 X: 18647213 (GRCh38) [ NCBI UCSC ] X: 18665333 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 14, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000330.4:c.304C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000321.1:p.Arg102Trp missense NM_001037343.2:c.2797+1123G>A intron variant NM_003159.3:c.2797+1123G>A intron variant NC_000023.11:g.18647213G>A NC_000023.10:g.18665333G>A NG_008475.1:g.226609G>A NG_008659.3:g.35236C>T LRG_702:g.35236C>T LRG_702t1:c.304C>T LRG_702p1:p.Arg102Trp O15537:p.Arg102Trp - Protein change
- R102W
- Other names
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- Canonical SPDI
- NC_000023.11:18647212:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CDKL5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1181 | 1934 | |
RS1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
121 | 859 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 8, 2021 | RCV000010565.16 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 15, 2023 | RCV000085268.16 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 30, 2015 | RCV000210291.10 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329503.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The R102W variant in the RS1 gene has been reported previously in association with X-linked retinoschisis (The Retinoschisis Consortium, 1998; Sauer CG et al. 1997; … (more)
The R102W variant in the RS1 gene has been reported previously in association with X-linked retinoschisis (The Retinoschisis Consortium, 1998; Sauer CG et al. 1997; Huang et al. 2014; O'Sullivan et al. 2012). In vitro functional studies demonstrated that the presence of the R102W variant results in intracellularly retained misfolded protein (Vijayasarathy et al. 2010). Another in vitro functional study confirmed that the retinoschisin protein is not secreted when the R102W variant is present (Wang et al., 2002). The R102W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R102W variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. Therefore, we interpret R102W to be a pathogenic variant. (less)
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Likely pathogenic
(Jan 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Juvenile retinoschisis
Affected status: yes
Allele origin:
unknown
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Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548020.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
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Likely pathogenic
(Apr 08, 2021)
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criteria provided, single submitter
Method: research
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Juvenile retinoschisis
Affected status: yes
Allele origin:
germline
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Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573556.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The RS1 c.304C>T variant was identified in an individual with retinitis pigmentosa with a presumed X-linked inheritance pattern. Through a review of available evidence we … (more)
The RS1 c.304C>T variant was identified in an individual with retinitis pigmentosa with a presumed X-linked inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Juvenile retinoschisis
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768670.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinoschisis (MIM#312700). (I) 0109 - This gene is associated with X-linked recessive disease, however, some affected females have also been reported (OMIM) (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1 heterozygote, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes, 0 hemizygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated coagulation factor 5/8 C-terminal domain (NCBI conserved domain). (I) 0702 – Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.R102Q and p.R102P alternative variants have previously been reported as pathogenic in patients with retinoschisis (ClinVar, PMIDs: 30652005, 28272453). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic in multiple individuals with retinoschisis (ClinVar, PMIDs: 9326935, 30652005, 30551202, 31725702). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant is result in a defect in protein secretion (PMID: 23453514). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001578976.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 102 of the RS1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 102 of the RS1 protein (p.Arg102Trp). This variant is present in population databases (rs61752067, gnomAD 0.008%). This missense change has been observed in individuals with X-linked juvenile retinoschisis (PMID: 9326935, 9618178, 16900931, 24634885, 30652005). ClinVar contains an entry for this variant (Variation ID: 9887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RS1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RS1 function (PMID: 12417531). This variant disrupts the p.Arg102 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 17615541, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 1997)
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no assertion criteria provided
Method: literature only
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RETINOSCHISIS 1, X-LINKED, JUVENILE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030791.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a family with X-linked juvenile retinoschisis (RS1; 312700), Sauer et al. (1997) identified a C-to-T transition in codon 102 of the XLRS1 gene, changing … (more)
In a family with X-linked juvenile retinoschisis (RS1; 312700), Sauer et al. (1997) identified a C-to-T transition in codon 102 of the XLRS1 gene, changing it from CGG (arg) to TGG (trp) (R102W). (less)
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Pathogenic
(Jan 30, 2015)
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no assertion criteria provided
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV000259096.1
First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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Retina International
Accession: SCV000117405.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
PHENOTYPE-GUIDED GENETIC TESTING OF PEDIATRIC INHERITED RETINAL DISEASE IN THE UNITED ARAB EMIRATES. | Khan AO | Retina (Philadelphia, Pa.) | 2020 | PMID: 31725702 |
Novel mutations in the RS1 gene in Japanese patients with X-linked congenital retinoschisis. | Kondo H | Human genome variation | 2019 | PMID: 30652005 |
Prospective Evaluation of Patients With X-Linked Retinoschisis During 18 Months. | Pennesi ME | Investigative ophthalmology & visual science | 2018 | PMID: 30551202 |
Genetic analysis and clinical features of X-linked retinoschisis in Chinese patients. | Hu QR | Scientific reports | 2017 | PMID: 28272453 |
Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. | Ellingford JM | Ophthalmology | 2016 | PMID: 26872967 |
R102W mutation in the RS1 gene responsible for retinoschisis and recurrent glaucoma. | Huang XF | International journal of ophthalmology | 2014 | PMID: 24634885 |
A phenotype-genotype correlation study of X-linked retinoschisis. | Vincent A | Ophthalmology | 2013 | PMID: 23453514 |
Molecular mechanisms leading to null-protein product from retinoschisin (RS1) signal-sequence mutants in X-linked retinoschisis (XLRS) disease. | Vijayasarathy C | Human mutation | 2010 | PMID: 20809529 |
Clinical features of X linked juvenile retinoschisis in Chinese families associated with novel mutations in the RS1 gene. | Li X | Molecular vision | 2007 | PMID: 17615541 |
Unusual phenotypic expression of an XLRS1 mutation in X-linked juvenile retinoschisis. | Dodds JA | Journal of child neurology | 2006 | PMID: 16900931 |
Molecular pathology of X linked retinoschisis: mutations interfere with retinoschisin secretion and oligomerisation. | Wang T | The British journal of ophthalmology | 2006 | PMID: 16361673 |
Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis. | Wang T | Human molecular genetics | 2002 | PMID: 12417531 |
Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium. | - | Human molecular genetics | 1998 | PMID: 9618178 |
Positional cloning of the gene associated with X-linked juvenile retinoschisis. | Sauer CG | Nature genetics | 1997 | PMID: 9326935 |
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Text-mined citations for rs61752067 ...
HelpRecord last updated Apr 20, 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.