X-18642089-C-T

Position:

• chrX-18642089-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.590G>A​(p.Arg197His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,447 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O: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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-18642089-C-T is Pathogenic according to our data. Variant chrX-18642089-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18642089-C-T is described in Lovd as [Pathogenic]. Variant chrX-18642089-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.590G>A	p.Arg197His	missense_variant	6/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.494G>A	p.Arg165His	missense_variant	4/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3918C>T		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-3918C>T		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.590G>A	p.Arg197His	missense_variant	6/6	1	NM_000330.4	ENSP00000369320	P1
CDKL5	ENST00000379989.6	c.2714-3918C>T		intron_variant		1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2714-3918C>T		intron_variant		1		ENSP00000369332
RS1	ENST00000476595.1	n.1081G>A		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111407 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33583

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183097 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67639

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 SAS 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: 9.11e-7 AC: 1 AN: 1098040 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363396

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: 0.0000247

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111407 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33583

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2017	The R197H missense variant in the RS1 gene has been reported previously in multiple unrelated individuals with X-linked retinoschisis (The Retinoschisis Consortium, 1998; Sadaka and Sisk, 2016; Sergeev et al., 2013). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R197H variant is a conservative amino acid substitution, which should be unlikely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in the same codon (R197S, R197C, R197P) and nearby residues (I194N, I195V, I199T, R200S, R200C, R200H) have been reported in the Human Gene Mutation Database in association with retinoschisis (Stenson et al., 2014; Inoue et al., 2000), supporting the functional importance of this region of the protein. We interpret R197H as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg197 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 10636421, 25799783, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RS1 function (PMID: 29851975). 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. ClinVar contains an entry for this variant (Variation ID: 98997). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 27246168, 29851975, 30652005). This variant is present in population databases (rs281865355, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 197 of the RS1 protein (p.Arg197His). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -

Juvenile retinoschisis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2016	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Retinoschisis juvenile X-linked 1, in X-linked Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Observed in multiple unrelated patients. (PMID:17631851,29081674,27246168,28450823,19390641). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:17631851). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of catalytic residue at R197 (P = 0.0064);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.97

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: rs281865355; hg19: chrX-18660209;