X-18642024-A-G

Variant names:

• chrX-18642024-A-G
• rs281865369
• NM_000330.4:c.655T>C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.95

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 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
RS1	NM_000330.4	c.655T>C	p.Cys219Arg	missense_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.559T>C	p.Cys187Arg	missense_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3983A>G		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3983A>G		intron_variant	Intron 18 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.655T>C	p.Cys219Arg	missense_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-3983A>G		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3983A>G		intron_variant	Intron 18 of 20	1		ENSP00000369332.3
RS1	ENST00000476595.1	n.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:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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:1 Other:1

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. -

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Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Other links and lift over

dbSNP: rs281865369; hg19: chrX-18660144;