X-18642023-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000330.4(RS1):​c.656G>A​(p.Cys219Tyr) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C219G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

RS1
NM_000330.4 missense

Scores

13
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

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]
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]

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ACMG classification

Classification made for transcript

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, 0.995
PP5
Variant X-18642023-C-T is Pathogenic according to our data. Variant chrX-18642023-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1700721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18642023-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RS1NM_000330.4 linkc.656G>A p.Cys219Tyr missense_variant Exon 6 of 6 ENST00000379984.4 NP_000321.1 O15537
RS1XM_047442337.1 linkc.560G>A p.Cys187Tyr missense_variant Exon 4 of 4 XP_047298293.1
CDKL5NM_001037343.2 linkc.2714-3984C>T intron_variant Intron 19 of 21 NP_001032420.1 O76039-1
CDKL5NM_003159.3 linkc.2714-3984C>T intron_variant Intron 18 of 20 NP_003150.1 O76039-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RS1ENST00000379984.4 linkc.656G>A p.Cys219Tyr missense_variant Exon 6 of 6 1 NM_000330.4 ENSP00000369320.3 O15537
CDKL5ENST00000379989.6 linkc.2714-3984C>T intron_variant Intron 19 of 21 1 ENSP00000369325.3 O76039-1
CDKL5ENST00000379996.7 linkc.2714-3984C>T intron_variant Intron 18 of 20 1 ENSP00000369332.3 O76039-1
RS1ENST00000476595.1 linkn.1147G>A non_coding_transcript_exon_variant Exon 5 of 5 1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Feb 10, 2022
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33090715, 32300273) -

Mar 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys219 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with retinoschisis (PMID: 32300273). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 219 of the RS1 protein (p.Cys219Tyr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.72
D
BayesDel_noAF
Pathogenic
0.80
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-8.6
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.94
MutPred
0.97
Gain of disorder (P = 0.0582);
MVP
1.0
MPC
2.1
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.96
gMVP
1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18660143; API