X-18647192-C-T

Position:

• chrX-18647192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000330.4(RS1):​c.325G>A​(p.Gly109Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G109E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 missense, splice_region
• Scores: Splicing: ADA: 0.9392
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57

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]

RS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a disulfide_bond (size 156) in uniprot entity XLRS1_HUMAN there are 39 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant X-18647192-C-T is Pathogenic according to our data. Variant chrX-18647192-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 940378.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.325G>A	p.Gly109Arg	missense_variant, splice_region_variant	4/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.229G>A	p.Gly77Arg	missense_variant, splice_region_variant	2/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2797+1102C>T		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2797+1102C>T		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.325G>A	p.Gly109Arg	missense_variant, splice_region_variant	4/6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2797+1102C>T		intron_variant		1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2797+1102C>T		intron_variant		1		ENSP00000369332.3
RS1	ENST00000476595.1	n.816G>A		splice_region_variant, non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 109 of the RS1 protein (p.Gly109Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (RS) (PMID: 9326935, 10234514, 15937075). ClinVar contains an entry for this variant (Variation ID: 940378). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RS1 function (PMID: 12417531). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift	Benign	0.11	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.89		Gain of MoRF binding (P = 0.0094);
MVP		0.98
MPC		1.8
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.85
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

LitVar

Other links and lift over

dbSNP: rs104894934; hg19: chrX-18665312;