rs61752067

chrX-18647213-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 3 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.00

Genes affected

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000330.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18647212-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-18647213-G-A is Pathogenic according to our data. Variant chrX-18647213-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18647213-G-A is described in Lovd as [Pathogenic]. Variant chrX-18647213-G-A is described in Lovd as [Likely_pathogenic].

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: 1 AN: 183299 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1097960 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
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. -

not provided Pathogenic:2 Other:1

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. -
not provided, no classification provided	literature only	Retina International	-	- -
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. -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.70
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Loss of methylation at R102 (P = 0.0176);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61752067; hg19: chrX-18665333; COSMIC: COSV66105902;