VCV000009895.16 - ClinVar

NM_000330.4(RS1):c.608C>T (p.Pro203Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000330.4(RS1):c.608C>T (p.Pro203Leu)

Variation ID: 9895 Accession: VCV000009895.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp22.13 X: 18642071 (GRCh38) [ NCBI UCSC ] X: 18660191 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Feb 14, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000330.4:c.608C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000321.1:p.Pro203Leu	missense
NM_001037343.2:c.2714-3936G>A		intron variant
NM_003159.3:c.2714-3936G>A		intron variant
NC_000023.11:g.18642071G>A
NC_000023.10:g.18660191G>A
NG_008475.1:g.221467G>A
NG_008659.3:g.40378C>T
LRG_702:g.40378C>T
LRG_702t1:c.608C>T	LRG_702p1:p.Pro203Leu
	O15537:p.Pro203Leu

... more HGVS ... less HGVS

Protein change

P203L

Other names

Canonical SPDI

NC_000023.11:18642070:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA226813 UniProtKB: O15537#VAR_008253 OMIM: 300839.0010 dbSNP: rs104894930 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CDKL5		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1258	2025
RS1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	124	876

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Juvenile retinoschisis	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 7, 2022	RCV000010573.17
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 17, 2023	RCV000085344.21
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Oct 3, 2018	RCV001074001.10
Retinoschisis	Likely pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003214.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 03, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239567.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (X-linked dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447633.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Retinoschisis (present) Sex: male
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001824580.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect with protein aggregation and defective secretion (Wu et al., 2003); Not observed in large population cohorts (gnomAD); In … (more) Published functional studies demonstrate a damaging effect with protein aggregation and defective secretion (Wu et al., 2003); Not observed 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: 9618178, 16167295, 19324861, 17515881, 30652005, 31456290, 33124204, 10450864, 10636740, 12746437) (less)
Likely pathogenic (Jan 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile retinoschisis Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580716.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4_MOD, PM6, PP1_MOD, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jun 09, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Juvenile retinoschisis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486492.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022	Publications: PubMed (9) PubMed: 17515881‚ 16167295‚ 18541843‚ 10636740‚ 10220153‚ 26356828‚ 10234514‚ 20061330‚ 9618178
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001578746.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 9618178‚ 10636740‚ 26356828‚ 28221463‚ 30652005‚ 22245991‚ 28559085 Comment: ClinVar contains an entry for this variant (Variation ID: 9895). This missense change has been observed in individuals with retinoschisis (PMID: 9618178, 10636740, 26356828, 28221463, … (more) ClinVar contains an entry for this variant (Variation ID: 9895). This missense change has been observed in individuals with retinoschisis (PMID: 9618178, 10636740, 26356828, 28221463, 30652005). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the RS1 protein (p.Pro203Leu). 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 disrupts the p.Pro203 amino acid residue in RS1. Other variant(s) that disrupt this residue have been observed in individuals with RS1-related conditions (PMID: 22245991, 28559085), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 01, 1999)	no assertion criteria provided Method: literature only	RETINOSCHISIS 1, X-LINKED, JUVENILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030799.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 10636740 Comment on evidence: In a Greek family with retinoschisis (RS1; 312700), Gehrig et al. (1999) reported a C-to-T transition at nucleotide 608 of the RS1 gene resulting in … (more) In a Greek family with retinoschisis (RS1; 312700), Gehrig et al. (1999) reported a C-to-T transition at nucleotide 608 of the RS1 gene resulting in the substitution of a leucine residue for a proline at position 203 (P203L) in the discoidin domain. (less)
Likely pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	retinoschisis Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161292.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000117481.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_XLRS:c.608C>T

Comment:

Published functional studies demonstrate a damaging effect with protein aggregation and defective secretion (Wu et al., 2003); Not observed 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: 9618178, 16167295, 19324861, 17515881, 30652005, 31456290, 33124204, 10450864, 10636740, 12746437)

Comment:

ClinVar contains an entry for this variant (Variation ID: 9895). This missense change has been observed in individuals with retinoschisis (PMID: 9618178, 10636740, 26356828, 28221463, 30652005). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 203 of the RS1 protein (p.Pro203Leu). 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 disrupts the p.Pro203 amino acid residue in RS1. Other variant(s) that disrupt this residue have been observed in individuals with RS1-related conditions (PMID: 22245991, 28559085), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel mutations in the RS1 gene in Japanese patients with X-linked congenital retinoschisis.	Kondo H	Human genome variation	2019	PMID: 30652005
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Detailed Morphological Changes of Foveoschisis in Patient with X-Linked Retinoschisis Detected by SD-OCT and Adaptive Optics Fundus Camera.	Akeo K	Case reports in ophthalmological medicine	2015	PMID: 26356828
Novel RS1 mutations associated with X-linked juvenile retinoschisis.	Yi J	International journal of molecular medicine	2012	PMID: 22245991
Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis.	Sergeev YV	Human molecular genetics	2010	PMID: 20061330
Retinal morphological changes of patients with X-linked retinoschisis evaluated by Fourier-domain optical coherence tomography.	Gerth C	Archives of ophthalmology (Chicago, Ill. : 1960)	2008	PMID: 18541843
Genetic variations in the hotspot region of RS1 gene in Indian patients with juvenile X-linked retinoschisis.	Suganthalakshmi B	Molecular vision	2007	PMID: 17515881
Identification of XLRS1 gene mutation (608C>T) in a Portuguese family with juvenile retinoschisis.	Teixeira C	European journal of ophthalmology	2005	PMID: 28221463
Identification of XLRS1 gene mutation (608C > T) in a Portuguese family with juvenile retinoschisis.	Teixeira C	European journal of ophthalmology	2005	PMID: 16167295
First molecular evidence for a de novo mutation in RS1 (XLRS1) associated with X linked juvenile retinoschisis.	Gehrig A	Journal of medical genetics	1999	PMID: 10636740
Three widespread founder mutations contribute to high incidence of X-linked juvenile retinoschisis in Finland.	Huopaniemi L	European journal of human genetics : EJHG	1999	PMID: 10234514
Identification of four novel mutations of the XLRS1 gene in Japanese patients with X-linked juvenile retinoschisis. Mutation in brief no. 234. Online.	Mashima Y	Human mutation	1999	PMID: 10220153
Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium.	-	Human molecular genetics	1998	PMID: 9618178
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Text-mined citations for rs104894930 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000330.4(RS1):c.608C>T (p.Pro203Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894930 ...