rs61753174

Variant names:

• chrX-18642105-G-A
• rs61753174
• NM_000330.4:c.574C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-18642105-G-A
• chrX-18642105-G-C
• chrX-18642105-G-T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.574C>T​(p.Pro192Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,878 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P192R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.60
• Publications: 17 publications found

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]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS1: Transcript NM_000330.4 (RS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chrX-18642105-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 98989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 0.96911 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked retinoschisis, retinoschisis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-18642105-G-A is Pathogenic according to our data. Variant chrX-18642105-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 98990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.574C>T	p.Pro192Ser	missense_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.478C>T	p.Pro160Ser	missense_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3902G>A		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3902G>A		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.574C>T	p.Pro192Ser	missense_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
RS1	ENST00000476595.1	n.1065C>T		non_coding_transcript_exon_variant	Exon 5 of 5	1
CDKL5	ENST00000379989.6	c.2714-3902G>A		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3902G>A		intron_variant	Intron 18 of 20	1		ENSP00000369332.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097878 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363238

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841809

Other (OTH) AF: 0.00 AC: 0 AN: 46080

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile retinoschisis Pathogenic:4

Nov 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2015

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 27, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4+PP3_Strong -

Retinal dystrophy Pathogenic:2

May 10, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 192 of the RS1 protein (p.Pro192Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9326935, 10533068, 28348004, 30551202, 30652005). ClinVar contains an entry for this variant (Variation ID: 98990). 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%. Experimental studies have shown that this missense change affects RS1 function (PMID: 20809529). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.95
Sift	Benign	0.15	T
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Loss of catalytic residue at P192 (P = 0.0024);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.95
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61753174; hg19: chrX-18660225;