X-18647212-C-T

Variant names:

• chrX-18647212-C-T
• rs61752068
• NM_000330.4:c.305G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 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 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 reviewed by expert panel P:13 O:1
• Conservation: PhyloP100: 7.57
• Publications: 33 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 Pathogenic. ClinVar VariationId is 9887.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.96911 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked retinoschisis, retinoschisis.
• 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 VariationId is 9896.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.305G>A	p.Arg102Gln	missense_variant	Exon 4 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.209G>A	p.Arg70Gln	missense_variant	Exon 2 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2797+1122C>T		intron_variant	Intron 20 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2797+1122C>T		intron_variant	Intron 19 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.305G>A	p.Arg102Gln	missense_variant	Exon 4 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1	n.796G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1
CDKL5	ENST00000379989.6	c.2797+1122C>T		intron_variant	Intron 20 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2797+1122C>T		intron_variant	Intron 19 of 20	1		ENSP00000369332.3

Frequencies

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

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

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183304 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3990

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 842093

Other (OTH) AF: 0.00 AC: 0 AN: 46062

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

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.00 AC: 0 AN: 10357

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5957

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52958

Other (OTH) AF: 0.00 AC: 0 AN: 1473

Alfa AF: 0.0000517 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile retinoschisis Pathogenic:6

Mar 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 19, 2025

ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000330.4(RS1):c.305G>A (p.Arg102Gln) is a missense variant encoding the substitution of arginine with glutamine at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00001261 among hemizygous individuals, with 5 variant alleles / 396,397 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting threshold of <0.000002 and BS1 threshold of >0.00002 and fails to meet these criteria. This variant has been reported in at least 6 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMID: 10589241, PMID: 12928282, PMID: 15937075, PMID: 17615541, PMID: 37317958, PS4). The variant has been reported to segregate with retinal dystrophy through >3 meioses in two families (PP1_Strong; PMID: 12928282, PMID: 15937075). HeLa cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 37317958, PS3_Supporting). The computational predictor REVEL gives a score of 0.983, which is above the ClinGen X-linked IRD VCEP threshold of >0.932 and predicts a damaging effect on RS1 function (PP3_Strong). The computational splicing predictor SpliceAI gives a delta score of 0.00 for all predictive splice changes, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. In summary, this variant is classified as pathogenic for X-linked retinoschisis based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RS1 Version 1.0.0: PS4, PP1_Strong, PP3_Strong, and PS3_Supporting.

May 06, 2014

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3 Other:1

Apr 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RS1: PM2, PM5, PM6, PS4:Moderate, PP1, PP4, PS3:Supporting

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Retinal dystrophy Pathogenic:2

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 29, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal disorders Pathogenic:1

Aug 20, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_moderate, PM2_moderate, PP3_supporting, PM5_moderate, PM1_supporting

RS1-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 (see for examples: RSC et al. 1998. PubMed ID: 9618178; Kondo et al. 2019. PubMed ID: 30652005; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S1, Karali et al. 2022. PubMed ID: 36460718). Additionally, a different substitution of this amino acid residue (p.Arg102Trp) has also been reported as causative for retinoschisis (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. 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
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
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.016	D
Vest4		0.99
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.97
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61752068; hg19: chrX-18665332;