X-18642024-A-G

Variant summary

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

The NM_000330.4(RS1):​c.655T>C​(p.Cys219Arg) 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
2
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 8.95
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, 0.996
PP5
Variant X-18642024-A-G is Pathogenic according to our data. Variant chrX-18642024-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18642024-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RS1NM_000330.4 linkc.655T>C p.Cys219Arg missense_variant Exon 6 of 6 ENST00000379984.4 NP_000321.1 O15537
RS1XM_047442337.1 linkc.559T>C p.Cys187Arg missense_variant Exon 4 of 4 XP_047298293.1
CDKL5NM_001037343.2 linkc.2714-3983A>G intron_variant Intron 19 of 21 NP_001032420.1 O76039-1
CDKL5NM_003159.3 linkc.2714-3983A>G 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.655T>C p.Cys219Arg missense_variant Exon 6 of 6 1 NM_000330.4 ENSP00000369320.3 O15537
CDKL5ENST00000379989.6 linkc.2714-3983A>G intron_variant Intron 19 of 21 1 ENSP00000369325.3 O76039-1
CDKL5ENST00000379996.7 linkc.2714-3983A>G intron_variant Intron 18 of 20 1 ENSP00000369332.3 O76039-1
RS1ENST00000476595.1 linkn.1146T>C 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:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinal dystrophy Pathogenic:2
Jan 01, 2018
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 09, 2017
Blueprint Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1Other:1
-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 25, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant disrupts the p.Cys219 amino acid residue in RS1. Other variant(s) that disrupt this residue have been observed in individuals with RS1-related conditions (PMID: 9618178, 20061330, 30652005), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with retinoschisis (PMID: 9618178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 99015). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 219 of the RS1 protein (p.Cys219Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.81
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-9.2
D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.97
Gain of MoRF binding (P = 0.0042);
MVP
1.0
MPC
2.2
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.98
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

LitVar

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

Other links and lift over

dbSNP: rs281865369; hg19: chrX-18660144; API