X-18647303-C-T

Variant names:

• chrX-18647303-C-T
• rs104894928
• NM_000330.4:c.214G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4 PP3_Moderate PP1_Strong PS3_Supporting PP4 PM1

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
• Clinical Significance: Pathogenic reviewed by expert panel P:18 O:1
• Conservation: PhyloP100: 7.57
• Publications: 51 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 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000330.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.214G>A	p.Glu72Lys	missense	Exon 4 of 6	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2797+1213C>T		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2797+1213C>T		intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.214G>A	p.Glu72Lys	missense	Exon 4 of 6	ENSP00000369320.3	O15537
	CDKL5	ENST00000379989.6	TSL:1	c.2797+1213C>T		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2797+1213C>T		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183440 AF XY: 0.0000147

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: 5 AN: 1097695 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363121

African (AFR) AF: 0.00 AC: 0 AN: 26383

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

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

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54125

European-Finnish (FIN) AF: 0.0000493 AC: 2 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841859

Other (OTH) AF: 0.00 AC: 0 AN: 46059

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Juvenile retinoschisis (9)
6	-	-	not provided (7)
2	-	-	Retinal dystrophy (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Benign	0.26	T
Sift4G	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.90		Gain of ubiquitination at E72 (P = 0.0101)
MVP		1.0
MPC		1.7
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.92
Mutation Taster		=11/89	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: rs104894928; hg19: chrX-18665423;