X-18642105-G-C

Position:

• chrX-18642105-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000330.4(RS1):​c.574C>G​(p.Pro192Ala) 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. P192L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 12 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, 0.967
• PP5: Variant X-18642105-G-C is Pathogenic according to our data. Variant chrX-18642105-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1346487.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-18642105-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.574C>G	p.Pro192Ala	missense_variant	6/6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.478C>G	p.Pro160Ala	missense_variant	4/4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3902G>C		intron_variant			NP_001032420.1
CDKL5	NM_003159.3	c.2714-3902G>C		intron_variant			NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.574C>G	p.Pro192Ala	missense_variant	6/6	1	NM_000330.4	ENSP00000369320	P1
CDKL5	ENST00000379989.6	c.2714-3902G>C		intron_variant		1		ENSP00000369325
CDKL5	ENST00000379996.7	c.2714-3902G>C		intron_variant		1		ENSP00000369332
RS1	ENST00000476595.1	n.1065C>G		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro192 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326935, 10533068, 28348004). 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 variant has been observed in individual(s) with X-linked retinoschisis (PMID: 15937075). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 192 of the RS1 protein (p.Pro192Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.92
Sift	Benign	0.073	T
Sift4G	Uncertain	0.036	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.81		Loss of catalytic residue at P192 (P = 0.0285);
MVP		0.94
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.94

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-18660225;