rs61752068

chrX-18647212-C-T

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.305G>A(p.Arg102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,208,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 5 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.57

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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-18647212-C-T is Pathogenic according to our data. 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. Variant chrX-18647212-C-T is described in Lovd as [Pathogenic]. Variant chrX-18647212-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RS1	NM_000330.4	c.305G>A	p.Arg102Gln	missense_variant	4/6	ENST00000379984.4
RS1	XM_047442337.1	c.209G>A	p.Arg70Gln	missense_variant	2/4
CDKL5	NM_001037343.2	c.2797+1122C>T		intron_variant
CDKL5	NM_003159.3	c.2797+1122C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RS1	ENST00000379984.4	c.305G>A	p.Arg102Gln	missense_variant	4/6	1	NM_000330.4	P1
CDKL5	ENST00000379989.6	c.2797+1122C>T		intron_variant		1
CDKL5	ENST00000379996.7	c.2797+1122C>T		intron_variant		1
RS1	ENST00000476595.1	n.796G>A		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110807 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32995

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183304 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098002 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363402

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: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000902 AC: 1 AN: 110807 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32995

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile retinoschisis Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	Counsyl	May 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009896). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17615541, 21701876, 24634885, 30652005). A different missense change at the same codon (p.Arg102Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009887). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 24, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 06, 2023	- -

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 102 of the RS1 protein (p.Arg102Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 17615541, 30652005). ClinVar contains an entry for this variant (Variation ID: 9896). 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%. 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, 24634885, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	RS1: PM2, PM5, PM6, PS4:Moderate, PP1, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Molecular modeling of the R102 position predicts a severe change which could affect the protein fold and thus is likely damaging to the protein structure/function (Sergeev et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9618178, 26894784, 28272453, 28348004, 34624300, 32531858, 35456481, 34828422, 17304551, 30652005, 31006083, 32783370, 34822951, 35309139, 34798543, 20061330) -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 29, 2019

- -

RS1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2023

The RS1 c.305G>A variant is predicted to result in the amino acid substitution p.Arg102Gln. This variant has been reported as causative for X-linked juvenile retinoschisis, XLRS (see for example RSC et al. 1998. PubMed ID: 9618178; Kondo et al. 2019. PubMed ID: 30652005). Additionally, a different substitution of the same amino acid (p.Arg102Trp) has been reported as causative for XLRS (Vijayasarathy et al. 2010. PubMed ID: 20809529; Kondo et al. 2019. PubMed ID: 30652005). This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-18665332-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9896). Given all the evidence, we interpret c.305G>A (p.Arg201Gln) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.91		Loss of methylation at R102 (P = 0.0176);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.97

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: rs61752068; hg19: chrX-18665332;