rs61752067
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000330.4(RS1):c.304C>T(p.Arg102Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000546 in 1,097,960 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102Q) has been classified as Pathogenic.
Frequency
Consequence
NM_000330.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RS1 | NM_000330.4 | c.304C>T | p.Arg102Trp | missense_variant | 4/6 | ENST00000379984.4 | |
RS1 | XM_047442337.1 | c.208C>T | p.Arg70Trp | missense_variant | 2/4 | ||
CDKL5 | NM_001037343.2 | c.2797+1123G>A | intron_variant | ||||
CDKL5 | NM_003159.3 | c.2797+1123G>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RS1 | ENST00000379984.4 | c.304C>T | p.Arg102Trp | missense_variant | 4/6 | 1 | NM_000330.4 | P1 | |
CDKL5 | ENST00000379989.6 | c.2797+1123G>A | intron_variant | 1 | |||||
CDKL5 | ENST00000379996.7 | c.2797+1123G>A | intron_variant | 1 | |||||
RS1 | ENST00000476595.1 | n.795C>T | non_coding_transcript_exon_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.00000546 AC: 1AN: 183299Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67747
GnomAD4 exome AF: 0.00000546 AC: 6AN: 1097960Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3AN XY: 363368
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Juvenile retinoschisis Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | 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 - |
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Molecular Genetics, University of Zurich | Jan 30, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1997 | - - |
not provided Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2017 | 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. - |
not provided, no classification provided | literature only | Retina International | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | 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. - |
Retinal dystrophy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Jan 30, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at