X-18647303-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4PP3_ModeratePP1_StrongPS3_SupportingPP4PM1

This summary comes from the ClinGen Evidence Repository: The NM_000330.4(RS1):c.214G>A variant is a missense variant encoding the substitution of Glutamic acid with Lysine at amino acid 72. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002508 among hemizygous individuals, with 1 variant alleles / 398646 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 0.921, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). 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. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID:12746437, PS3_Supporting). This variant p.Glu72Lys, of the RS1 gene, is an established residue involved in cross-linking the adjacent RS1 subunit by the ClinGen X-linked IRD VCEP (PMID:27114531, PM1). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_Strong; PMID:11246454, 38317323, 19324861). 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 (PMID:23288992, PP4). This variant has been reported in at least 6 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 28348004, 19324861, 22245991, 32531858, 29851975, 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_moderate, PP1_strong, PP4, PS4, PS3_supporting, and PM1 (date of approval 01/24/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226621/MONDO:0010725/126

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000046 ( 0 hom. 1 hem. )

Consequence

RS1
NM_000330.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 7.57

Publications

51 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 14 ACMG points.

PS3

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

PS4

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

PM1

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.214G>A	p.Glu72Lys	missense_variant	Exon 4 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 2 of 4		XP_047298293.1
CDKL5	NM_001037343.2 link	c.2797+1213C>T		intron_variant	Intron 20 of 21		NP_001032420.1
CDKL5	NM_003159.3 link	c.2797+1213C>T		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.214G>A	p.Glu72Lys	missense_variant	Exon 4 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1 link	n.705G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1
CDKL5	ENST00000379989.6 link	c.2797+1213C>T		intron_variant	Intron 20 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7 link	c.2797+1213C>T		intron_variant	Intron 19 of 20	1		ENSP00000369332.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183440

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1097695

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363121

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26383

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54125

European-Finnish (FIN)

AF:

0.0000493

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3944

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841859

Other (OTH)

AF:

0.00

AC:

AN:

46059

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Juvenile retinoschisis

Pathogenic:8

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

xperimental studies have shown that this missense change affects RS1 function (PS3, PMID: 20809529;20061330). REVEL score is 0.921 (PP3_mod). This variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1) Other changes at this amino acid residue have been classified as pathogenic (PM5, p.Glu72Gln; p.Glu72Val; p.Glu72Lys; p.Glu72Gly). RS1 mutations are specific to retinoschisis phenotypes (PP4) -

Jul 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 11, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS3,PS4,PM5_STR,PM2_SUP,PP3,PP4 -

Nov 15, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000330.3(RS1):c.214G>A(E72K) is classified as pathogenic in the context of X-linked juvenile retinoschisis. Sources cited for classification include the following: PMID 20061330, 10922205, 618178, 19390641, 10533068, 10234514 and 20809529. Classification of NM_000330.3(RS1):c.214G>A(E72K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Nov 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM5,PP2,PP3,PP4. This variant was detected in hemizygous state. -

Mar 19, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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.214G>A variant is a missense variant encoding the substitution of Glutamic acid with Lysine at amino acid 72. This variant is present in gnomAD v.4.1.0 at a frequency of 0.000002508 among hemizygous individuals, with 1 variant alleles / 398646 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 0.921, which is within the ClinGen X-linked IRD VCEP range between 0.931 to 0.773 and predicts a damaging effect on RS1 function (PP3_moderate). 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. HEK293 cells exogenously expressing the variant exhibit loss of RS1 secretion into the medium relative to the wild-type control (PMID: 12746437, PS3_Supporting). This variant p.Glu72Lys, of the RS1 gene, is an established residue involved in cross-linking the adjacent RS1 subunit by the ClinGen X-linked IRD VCEP (PMID: 27114531, PM1). The variant has been reported to segregate with retinal dystrophy through at least 3 meioses in the same family (PP1_Strong; PMID: 11246454, 38317323, 19324861). 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 (PMID: 23288992, PP4). This variant has been reported in at least 6 apparently unrelated probands meeting one of the PS4 requirements of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 28348004, 19324861, 22245991, 32531858, 29851975, 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_moderate, PP1_strong, PP4, PS4, PS3_supporting, and PM1 (date of approval 01/24/2025). -

Jun 23, 2023

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%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009888 /PMID: 9618178). Different missense changes at the same codon (p.Glu72Asp, p.Glu72Gln, p.Glu72Gly, p.Glu72Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009889, VCV000098916, VCV000992968, VCV001994509 /PMID: 11295123, 17631851, 28272453, 9618178). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:6Other:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RS1: PS4, PM1, PM2, PM5, PP3, PP4 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 20, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with misfolding of the discoidin domain, which results in the formation of high molecular mass aggregates in the cell (Vijayasarathy et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10234514, 31087526, 20809529, 20061330, 27788217, 23288992, 22245536, 19324861, 22245991, 29081674, 27798099, 9618178, 30652005, 33781268, 33460243) -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 72 of the RS1 protein (p.Glu72Lys). This variant is present in population databases (rs104894928, gnomAD 0.01%). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 28272453, 30652005). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9888). 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: 20809529). This variant disrupts the p.Glu72 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 28272453). 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. -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:2

Feb 22, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 20, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.214G>A (p.E72K) alteration is located in exon 4 (coding exon 4) of the RS1 gene. This alteration results from a G to A substitution at nucleotide position 214, causing the glutamic acid (E) at amino acid position 72 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/183440) total alleles studied. The highest observed frequency was 0.006% (1/16007) of European (Finnish) alleles. This variant is a common founder mutation and has been detected in individuals with X-linked juvenile retinoschisis (The Retinoschisis Consortium, 1998; Hiriyanna, 1999; Huopaniemi, 1999; Eksandh, 2000; Riveiro-Alvarez, 2009; Kim, 2009; Skorczyk, 2012; Wang, 2016; Hu, 2017; Sudha, 2018; Avela, 2019; Kondo, 2019; Huang, 2020; Bai, 2021; Hahn, 2022; Bender, 2022). This amino acid position is highly conserved in available vertebrate species. Functional and structural analysis suggest this alteration disrupts the local structure, but does not significantly impair secretion of the mutant protein (Wu, 2003; Sergeev, 2010; Vijayasarathy, 2010). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.67

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

PhyloP100

7.6

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.92

Sift

Benign

0.26

Sift4G

Benign

0.089

Polyphen

1.0

Vest4

0.96

MutPred

0.90

Gain of ubiquitination at E72 (P = 0.0101);

MVP

1.0

MPC

1.7

ClinPred

0.85

GERP RS

5.4

Varity_R

0.83

gMVP

0.92

Mutation Taster

=11/89

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