NM_000330.4(RS1):c.421C>T (p.Arg141Cys) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Oct 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000085300.36

Allele description [Variation Report for NM_000330.4(RS1):c.421C>T (p.Arg141Cys)]

NM_000330.4(RS1):c.421C>T (p.Arg141Cys)

Genes:

CDKL5:cyclin dependent kinase like 5 [Gene - OMIM - HGNC]
RS1:retinoschisin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.13

Genomic location:

Preferred name:

NM_000330.4(RS1):c.421C>T (p.Arg141Cys)

HGVS:

NC_000023.11:g.18644531G>A
NG_008475.1:g.223927G>A
NG_008659.3:g.37918C>T
NM_000330.4:c.421C>TMANE SELECT
NM_001037343.2:c.2714-1476G>A
NM_003159.3:c.2714-1476G>A
NP_000321.1:p.Arg141Cys
NP_000321.1:p.Arg141Cys
LRG_702t1:c.421C>T
LRG_702:g.37918C>T
LRG_702p1:p.Arg141Cys
NC_000023.10:g.18662651G>A
NM_000330.3:c.421C>T
O15537:p.Arg141Cys

Protein change:

R141C

Links:

UniProtKB: O15537#VAR_008231; dbSNP: rs61752158

NCBI 1000 Genomes Browser:

rs61752158

Molecular consequence:

NM_001037343.2:c.2714-1476G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_003159.3:c.2714-1476G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000330.4:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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LOC105172719 [Sesamum indicum]
LOC105172719 [Sesamum indicum]
Gene ID:105172719

Gene
J7337_010708 [Fusarium musae]
J7337_010708 [Fusarium musae]
Gene ID:68318564

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000117437	Retina International	no classification provided	not provided	unknown	not provided
SCV001246522	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Nov 1, 2018)	germline	clinical testing	Citation Link,
SCV001578974	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28559085, 9618178, 10636429, 30450322, 30652005, 28492532
SCV002574248	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 14, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.

Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA.

Ophthalmology. 2017 Sep;124(9):1314-1331. doi: 10.1016/j.ophtha.2017.04.008. Epub 2017 May 27.

PubMed [citation]

PMID:: 28559085
PMCID:: PMC5565704

Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. The Retinoschisis Consortium.

[No authors listed]

Hum Mol Genet. 1998 Jul;7(7):1185-92.

PubMed [citation]

PMID:: 9618178

See all PubMed Citations (6)

Details of each submission

From Retina International, SCV000117437.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001246522.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001578974.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 141 of the RS1 protein (p.Arg141Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked retinoschisis (PMID: 9618178, 28559085). ClinVar contains an entry for this variant (Variation ID: 98959). 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.Arg141 amino acid residue in RS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618178, 10636429, 30450322, 30652005). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002574248.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20061330, 17987333, 19324861, 15937075, 28559085, 32531858, 31429209, 34828422, 9618178, 19093009, 35456481, 31456290)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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