X-18642105-G-A

Position:

• chrX-18642105-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.574C>T​(p.Pro192Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,878 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P192L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain F5/8 type C (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, 0.987
• PP5: Variant X-18642105-G-A is Pathogenic according to our data. Variant chrX-18642105-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 98990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18642105-G-A is described in Lovd as [Pathogenic]. Variant chrX-18642105-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.574C>T	p.Pro192Ser	missense_variant	6/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.478C>T	p.Pro160Ser	missense_variant	4/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3902G>A		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-3902G>A		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.574C>T	p.Pro192Ser	missense_variant	6/6	1	NM_000330.4	ENSP00000369320	P1
CDKL5	ENST00000379989.6	c.2714-3902G>A		intron_variant		1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2714-3902G>A		intron_variant		1		ENSP00000369332
RS1	ENST00000476595.1	n.1065C>T		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097878 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile retinoschisis Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Likely pathogenic, no assertion criteria provided	literature only	Counsyl	Jan 22, 2015	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 192 of the RS1 protein (p.Pro192Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9326935, 10533068, 28348004, 30551202, 30652005). ClinVar contains an entry for this variant (Variation ID: 98990). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.95
Sift	Benign	0.15	T
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Loss of catalytic residue at P192 (P = 0.0024);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs61753174; hg19: chrX-18660225;