rs104894929

Variant names:

• chrX-18642012-A-C
• rs104894929
• NM_000330.4:c.667T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-18642012-A-C
• chrX-18642012-A-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000330.4(RS1):​c.667T>G​(p.Cys223Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. C223W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.95
• Publications: 0 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000330.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-18642010-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4279587.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, 0.931
• PP5: Variant X-18642012-A-C is Pathogenic according to our data. Variant chrX-18642012-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1511265.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.667T>G	p.Cys223Gly	missense_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.571T>G	p.Cys191Gly	missense_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3995A>C		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3995A>C		intron_variant	Intron 18 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.667T>G	p.Cys223Gly	missense_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1	n.1158T>G		non_coding_transcript_exon_variant	Exon 5 of 5	1
CDKL5	ENST00000379989.6	c.2714-3995A>C		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3995A>C		intron_variant	Intron 18 of 20	1		ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile retinoschisis Pathogenic:1

Sep 19, 2025

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

NM_000330.4(RS1):c.667T>G (p.Cys223Gly) is a missense variant encoding the substitution of cysteine with glycine at amino acid 223. Another missense variant in the same codon, NM_000330.4(RS1):c.668G>C (p.Cys223Ser), (PMID: 12746437) has been classified as likely pathogenic for X-linked retinoschisis by the ClinGen X-linked IRD VCEP, while no benign missense variants have been identified in this codon. The present variant has a higher Grantham’s distance (159) than the comparison variant (112), and SpliceAI has been used to confirm that neither variant has a predicted impact on RS1 splicing (PM5_Supporting). This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.951, 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, which is below the ClinGen X-linked IRD VCEP threshold of ≥0.2 and does not predict that the variant disrupts RS1 splicing. This variant is a missense substitution affecting a critical amino acid residue involved in disulfide bridge formation as defined by the ClinGen X-linked IRD VCEP (PMID: 26812435). However, the PP3_Strong code has been met, which is ineligible to be used in combination with the PM1 code at any strength, so the PM1 code was not met. In summary, this variant is classified as likely 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: PM2_Supporting, PP3_ Strong, and PM5_Supporting.

not provided Pathogenic:1

Aug 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RS1-related conditions. 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. This variant disrupts the p.Cys223 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10533068, 16361673, 30652005; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces cysteine with glycine at codon 223 of the RS1 protein (p.Cys223Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Vest4		0.80
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.79
gMVP		1.0
Mutation Taster		=18/82	disease causing

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: rs104894929; hg19: chrX-18660132;