ClinVar Genomic variation as it relates to human health
NM_001830.4(CLCN4):c.2152C>T (p.Arg718Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001830.4(CLCN4):c.2152C>T (p.Arg718Trp)
Variation ID: 209116 Accession: VCV000209116.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.2 X: 10220837 (GRCh38) [ NCBI UCSC ] X: 10188877 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 4, 2016 Feb 14, 2024 May 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001830.4:c.2152C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001821.2:p.Arg718Trp missense NM_001256944.2:c.1870C>T NP_001243873.1:p.Arg624Trp missense NC_000023.11:g.10220837C>T NC_000023.10:g.10188877C>T NG_012496.1:g.68893C>T - Protein change
- R718W, R624W
- Other names
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- Canonical SPDI
- NC_000023.11:10220836:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on transport function of protein Variation Ontology [VariO:0009]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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CLCN4 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
588 | 761 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2016 | RCV000239734.3 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 27, 2022 | RCV000721130.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 31, 2023 | RCV000816910.9 | |
See cases
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no classifications from unflagged records (1) |
no classifications from unflagged records
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Apr 23, 2024 | RCV002252041.3 |
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
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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
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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
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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. |
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Pathogenic
(Mar 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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CLCN4-related disorder
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Sydney Children's Hospital, SCHN
Accession: SCV000245785.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
Comment:
De novo variant. Clinical phenotype consistent with case series of individuals with CLCN4 related disorder.
Number of individuals with the variant: 1
Clinical Features:
intellectual disability (present)
Family history: no
Sex: female
Ethnicity/Population group: Hispanic
Geographic origin: Mexico
Tissue: Blood
Comment on evidence:
Affects highly conserved amino acid in critical cystathionine-β-synthase domain. Not listed in ExAC. No other cause identified on comprehensive genetic investigations. CADD score 23.8. Reduced … (more)
Affects highly conserved amino acid in critical cystathionine-β-synthase domain. Not listed in ExAC. No other cause identified on comprehensive genetic investigations. CADD score 23.8. Reduced current when heterologously expressed in Xenopus oocytes (less)
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked 49
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976771.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PP2, PP3, PP5
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked 49
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058687.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542, PS2_S). Same nucleotide change resulting in same amino acid … (more)
The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000209116, PMID:26633542, PS1_S). A different missense change at the same codon has been reported to be associated with CLCN4 related disorder (ClinVar ID: VCV000521940, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.874, PP3_P). A missense variant is a common mechanism associated with Raynaud-Claes syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Autism (present) , Intellectual disability (present)
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Pathogenic
(Feb 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002069088.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, X-linked 49
Affected status: yes
Allele origin:
germline
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Gene2Care/ Palmer Lab, University of New South Wales
Accession: SCV002525721.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(May 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000957439.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). 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 CLCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 209116). This variant is also known as p.R624W. This missense change has been observed in individual(s) with CLCN4-related disease (PMID: 26633542, 27550844, 29314583). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the CLCN4 protein (p.Arg718Trp). (less)
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Pathogenic
(Nov 07, 2018)
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no assertion criteria provided
Method: literature only
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RAYNAUD-CLAES SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000852018.1
First in ClinVar: Nov 12, 2018 Last updated: Nov 12, 2018 |
Comment on evidence:
In a 15-year-old Scottish girl (Family M) with severe intellectual disability and a history of brief absence seizures (MRXSRC; 300114), Palmer et al. (2018) identified … (more)
In a 15-year-old Scottish girl (Family M) with severe intellectual disability and a history of brief absence seizures (MRXSRC; 300114), Palmer et al. (2018) identified a de novo C-to-T transition (chrX:10188877C-T) in the CLCN4 gene, resulting in an arg718-to-trp (R718W) substitution within the second cytosolic cystathionine-beta-synthase domain. The patient was nonverbal, drooled, and exhibited self-abusive behavior. No X-inactivation studies were performed. Expression of the variant in Xenopus oocytes showed reduced steady-state current compared to wildtype. (less)
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Uncertain significance
(Feb 03, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523491.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PM2, PP2, PP5
Clinical Features:
Neurodevelopmental abnormality (present) , Abnormality of mental function (present)
Geographic origin: Brazil
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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effect on transport function of protein
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Gene2Care/ Palmer Lab, University of New South Wales
Accession: SCV002525721.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel mutations and phenotypes of epilepsy-associated genes in epileptic encephalopathies. | Zhou P | Genes, brain, and behavior | 2018 | PMID: 29314583 |
De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females. | Palmer EE | Molecular psychiatry | 2018 | PMID: 27550844 |
Clinical application of whole-exome sequencing across clinical indications. | Retterer K | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633542 |
Text-mined citations for rs879255584 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.