X-18647212-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000330.4(RS1):c.305G>A(p.Arg102Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,208,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000082 ( 0 hom. 5 hem. )

Consequence

RS1
NM_000330.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 7.57

Variant links:

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]

RS1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant X-18647212-C-T is Pathogenic according to our data. Variant chrX-18647212-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18647212-C-T is described in Lovd as [Pathogenic]. Variant chrX-18647212-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4 link	c.305G>A	p.Arg102Gln	missense_variant	Exon 4 of 6	ENST00000379984.4	NP_000321.1	O15537
RS1	XM_047442337.1 link	c.209G>A	p.Arg70Gln	missense_variant	Exon 2 of 4		XP_047298293.1
CDKL5	NM_001037343.2 link	c.2797+1122C>T		intron_variant	Intron 20 of 21		NP_001032420.1	O76039-1
CDKL5	NM_003159.3 link	c.2797+1122C>T		intron_variant	Intron 19 of 20		NP_003150.1	O76039-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RS1	ENST00000379984.4 link	c.305G>A	p.Arg102Gln	missense_variant	Exon 4 of 6	1	NM_000330.4	ENSP00000369320.3	O15537
CDKL5	ENST00000379989.6 link	c.2797+1122C>T		intron_variant	Intron 20 of 21	1		ENSP00000369325.3	O76039-1
CDKL5	ENST00000379996.7 link	c.2797+1122C>T		intron_variant	Intron 19 of 20	1		ENSP00000369332.3	O76039-1
RS1	ENST00000476595.1 link	n.796G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32995

show subpopulations

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:

AN:

183304

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67740

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1098002

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363402

show subpopulations

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:

0.0000107

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110807

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32995

show subpopulations

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

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Juvenile retinoschisis

Pathogenic:5

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009896). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17615541, 21701876, 24634885, 30652005). A different missense change at the same codon (p.Arg102Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009887). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

May 06, 2014

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 15, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3Other:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RS1: PM2, PM5, PM6, PS4:Moderate, PP1, PP4, PS3:Supporting -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Molecular modeling of the R102 position predicts a severe change which could affect the protein fold and thus is likely damaging to the protein structure/function (Sergeev et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9618178, 26894784, 28272453, 28348004, 34624300, 32531858, 35456481, 34828422, 17304551, 30652005, 31006083, 32783370, 34822951, 35309139, 34798543, 20061330) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 102 of the RS1 protein (p.Arg102Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 17615541, 30652005). ClinVar contains an entry for this variant (Variation ID: 9896). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RS1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg102 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 24634885, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:2

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RS1-related disorder

Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RS1 c.305G>A variant is predicted to result in the amino acid substitution p.Arg102Gln. This variant has been reported as causative for X-linked juvenile retinoschisis (see for examples: RSC et al. 1998. PubMed ID: 9618178; Kondo et al. 2019. PubMed ID: 30652005; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S1, Karali et al. 2022. PubMed ID: 36460718). Additionally, a different substitution of this amino acid residue (p.Arg102Trp) has also been reported as causative for retinoschisis (Vijayasarathy et al. 2010. PubMed ID: 20809529; Kondo et al. 2019. PubMed ID: 30652005). This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9896). Given all the evidence, we interpret c.305G>A (p.Arg201Gln) as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.69

BayesDel_noAF

Pathogenic

0.76

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.99

MutPred

0.91

Loss of methylation at R102 (P = 0.0176);

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

5.4

Varity_R

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over