chrX-18647192-C-G

Position:

• chrX-18647192-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_000330.4(RS1):​c.325G>C​(p.Gly109Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,097,903 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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)
  • Exomes 𝑓: 0.0000091 (0 hom. 3 hem.)
• Consequence: RS1 NM_000330.4 missense, splice_region
• Scores: Splicing: ADA: 0.9547
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 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]

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
• 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-18647192-C-G is Pathogenic according to our data. Variant chrX-18647192-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18647192-C-G is described in Lovd as [Pathogenic]. Variant chrX-18647192-C-G is described in Lovd as [Likely_pathogenic].
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183100 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67602

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: 0.000188

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097903 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363337

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: 0.000222

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 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	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2019	The G109R variant has been report in association with X-linked juvenile retinoschisis (Huopaniemi et al., 1999; Sauer et al., 1997). In vitro functional studies demonstrated that the presence of the G109R variant resulted in no secretion of the RS1 protein and intracellular retention of the protein (Wang et al., 2002). The G109R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G109R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Therefore, G109R is interpreted to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 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 present in population databases (rs104894934, gnomAD 0.02%). This missense change has been observed in individuals with retinoschisis (PMID: 9326935, 31087526). ClinVar contains an entry for this variant (Variation ID: 9891). 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. -

Juvenile retinoschisis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

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	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.88	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		0.80	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.88
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;