NM_000330.4:c.304C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS4PP1_StrongPP3_StrongPP4

This summary comes from the ClinGen Evidence Repository: The NM_000330.4(RS1):c.304C>T variant is a missense variant encoding the substitution of Arginine with Tryptophan at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.958, 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 0.01 Acceptor Gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through 3 meioses in a family including two affected brothers and 5 other affected members (PP1_strong; PMID:36695495, 9326935, 16901436, 24634885). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (5 points, PMID:24634885, PP4). This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 33124204, 9326935, 22245991, 36695495, 28348004, 35456481, PS4). 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: PP3_strong, PP1_strong, PS4, and PP4 (date of approval 01/24/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226667/MONDO:0010725/126

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000055 ( 0 hom. 3 hem. )

Consequence

RS1
NM_000330.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 3.00

Publications

38 publications found

Variant links:

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]

RS1 links:

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

CDKL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RS1	NM_000330.4 link	c.304C>T	p.Arg102Trp	missense_variant	Exon 4 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1 link	c.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 4		XP_047298293.1
CDKL5	NM_001037343.2 link	c.2797+1123G>A		intron_variant	Intron 20 of 21		NP_001032420.1
CDKL5	NM_003159.3 link	c.2797+1123G>A		intron_variant	Intron 19 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RS1	ENST00000379984.4 link	c.304C>T	p.Arg102Trp	missense_variant	Exon 4 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1 link	n.795C>T		non_coding_transcript_exon_variant	Exon 3 of 5	1
CDKL5	ENST00000379989.6 link	c.2797+1123G>A		intron_variant	Intron 20 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7 link	c.2797+1123G>A		intron_variant	Intron 19 of 20	1		ENSP00000369332.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183299

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000546

AC:

AN:

1097960

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54137

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3988

European-Non Finnish (NFE)

AF:

0.00000713

AC:

AN:

842061

Other (OTH)

AF:

0.00

AC:

AN:

46060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Juvenile retinoschisis

Pathogenic:5

Oct 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 19, 2025

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

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000330.4(RS1):c.304C>T variant is a missense variant encoding the substitution of Arginine with Tryptophan at amino acid 102. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000008256 among hemizygous individuals, with 3 variant alleles / 363368 total hemizygous alleles, which is between the ClinGen X-linked IRD VCEP PM2_Supporting and BS1 thresholds of <0.000002 and >0.00002 and fails to meet these criteria. The computational predictor REVEL gives a score of 0.958, 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 0.01 Acceptor Gain, which is below the ClinGen X-linked IRD VCEP threshold of >0.2 and does not predict that the variant disrupts RS1 splicing. The variant has been reported to segregate with retinal dystrophy through 3 meioses in a family including two affected brothers and 5 other affected members (PP1_strong; PMID: 36695495, 9326935, 16901436, 24634885). At least one proband harboring this variant exhibits a phenotype including appearance of schisis and reduced visual acuity before age 13 years, which together are specific for X-linked retinoschisis (5 points, PMID: 24634885, PP4). This variant has been reported in at least 5 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 33124204, 9326935, 22245991, 36695495, 28348004, 35456481, PS4). 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: PP3_strong, PP1_strong, PS4, and PP4 (date of approval 01/24/2025).

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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.

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2Other:1

Oct 14, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26043410, 34624300, 32531858, 24634885, 35456481, 31725702, 35456422, 16361673, 9326935, 20809529, 25894957, 16900931, 30608181, 30652005, 31141763, 22581970, 33090715, 34822951, 36377647, 33124204, 36729443, 36284460, 34645606, 34906470, 12417531, 9618178)

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Dec 24, 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 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). 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%. 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:2

Jan 01, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 30, 2015

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Retinoschisis

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS3,PM3,PP1,PM2,PP3,PM5

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.70

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

3.0

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Vest4

0.98

ClinPred

0.99

GERP RS

4.6

Varity_R

0.94

gMVP

0.98

Mutation Taster

=24/75

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over