rs1057516744

Variant names:

• chrX-18644454-G-T
• rs1057516744
• NM_000330.4:c.498C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2_Supporting PS4_Supporting PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000330.4(RS1):c.498C>A variant is a nonsense variant in amino acid 166, which results in a premature stop codon and causes a truncated protein. This variant is absent from hemizygous individuals in gnomAD v4.1.0 (PM2_Supporting). This is a nonsense variant that introduces a premature stop codon between amino acids 1-223 that is predicted to either trigger nonsense-mediated decay or to disrupt a critical C-terminal region required for proper multimerization of RS1 (PVS1, PMID:19849666). This variant has been reported in at least 2 apparently unrelated probands meeting the PS4 requirement of a male diagnosed with X-linked retinoschisis (PMIDs: 30025115, 32860923, PS4_Supporting). 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: PM2_supporting, PVS1, and PS4_supporting (date of approval 01/24/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16042049/MONDO:0010725/126

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 2.46
• Publications: 1 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 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	NM_000330.4	MANE Select	c.498C>A	p.Tyr166*	stop_gained	Exon 5 of 6	NP_000321.1
	CDKL5	NM_001037343.2		c.2714-1553G>T		intron	N/A	NP_001032420.1
	CDKL5	NM_003159.3		c.2714-1553G>T		intron	N/A	NP_003150.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.498C>A	p.Tyr166*	stop_gained	Exon 5 of 6	ENSP00000369320.3
	RS1	ENST00000476595.1	TSL:1	n.989C>A		non_coding_transcript_exon	Exon 4 of 5
	CDKL5	ENST00000379989.6	TSL:1	c.2714-1553G>T		intron	N/A	ENSP00000369325.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Juvenile retinoschisis (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.5
Vest4		0.99
GERP RS		-1.7
Mutation Taster		=14/186	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: rs1057516744; hg19: chrX-18662574;