ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.1592C>T (p.Ala531Val)
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
-
NM_000083.3(CLCN1):c.1592C>T (p.Ala531Val)
Variation ID: 21040 Accession: VCV000021040.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 143341938 (GRCh38) [ NCBI UCSC ] 7: 143039031 (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 Mar 5, 2024 Feb 20, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000083.3:c.1592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Ala531Val missense NR_046453.2:n.1547C>T non-coding transcript variant NC_000007.14:g.143341938C>T NC_000007.13:g.143039031C>T NG_009815.2:g.30813C>T - Protein change
- A531V
- Other names
- -
- Canonical SPDI
- NC_000007.14:143341937:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | ||
---|---|---|---|---|---|---|
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. |
|||
CLCN1 | - | - |
GRCh38 GRCh37 |
1357 | 1506 |
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. |
---|---|---|---|---|
not provided (1) |
no classification provided
|
- | RCV000020102.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000638249.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 7, 2019 | RCV000711222.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 20, 2024 | RCV002267607.3 |
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
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
(Apr 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics Inc
Accession: SCV000841554.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
Pathogenic
(Jul 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715973.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_moderate, PM3, PP1, PP3
Number of individuals with the variant: 1
|
|
Pathogenic
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020372.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: CLCN1 c.1592C>T (p.Ala531Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: CLCN1 c.1592C>T (p.Ala531Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251370 control chromosomes, exclusively at a frequency of 4.4e-05 (i.e., 11 heterozygotes) within the Finnish subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1592C>T has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g., Sun_2002, Modoni_2011). Additionally, the variant was identified in several apparent heterozygotes affected with myotonia and latent myotonia, but was observed in unaffected heterozygous carriers as well, suggesting this variant may also cause autosomal dominant disease although with reduced penetrance (e.g., Sun_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21221019, 11840191). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Feb 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004697554.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
Pathogenic
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal dominant form
Congenital myotonia, autosomal recessive form
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811023.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital myotonia, autosomal recessive form
Congenital myotonia, autosomal dominant form
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000759735.6
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 531 of the CLCN1 protein (p.Ala531Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 531 of the CLCN1 protein (p.Ala531Val). This variant is present in population databases (rs80356704, gnomAD 0.04%). This missense change has been observed in individual(s) with myotonia congenita (PMID: 10430417, 11840191, 21221019, 22094069, 23933576; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21040). 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 CLCN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 17990293, 23424641, 23933576, 26021757, 27580824). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Apr 06, 2022)
|
no assertion criteria provided
Method: research
|
Congenital myotonia, autosomal recessive form
Affected status: yes
Allele origin:
germline
|
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002549783.1
First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Batten-Turner congenital myopathy
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040422.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Associated with autosomal recessive and autosomal dominant mode of inheritance
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Myotonia Congenita. | Adam MP | - | 2021 | PMID: 20301529 |
Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90β. | Peng YJ | Scientific reports | 2016 | PMID: 27580824 |
The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels. | Chen YA | Scientific reports | 2015 | PMID: 26021757 |
Truncating CLCN1 mutations in myotonia congenita: variable patterns of inheritance. | Richardson RC | Muscle & nerve | 2014 | PMID: 23893571 |
Functional characterization of ClC-1 mutations from patients affected by recessive myotonia congenita presenting with different clinical phenotypes. | Desaphy JF | Experimental neurology | 2013 | PMID: 23933576 |
Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene. | Mazón MJ | Neuromuscular disorders : NMD | 2012 | PMID: 22094069 |
Low-rate repetitive nerve stimulation protocol in an Italian cohort of patients affected by recessive myotonia congenita. | Modoni A | Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society | 2011 | PMID: 21221019 |
High frequency of co-segregating CLCN1 mutations among myotonic dystrophy type 2 patients from Finland and Germany. | Suominen T | Journal of neurology | 2008 | PMID: 18807109 |
Dosage effect of a dominant CLCN1 mutation: a novel syndrome. | Bernard G | Journal of child neurology | 2008 | PMID: 18263754 |
F413C and A531V but not R894X myotonia congenita mutations cause defective endoplasmic reticulum export of the muscle-specific chloride channel CLC-1. | Papponen H | Muscle & nerve | 2008 | PMID: 17990293 |
Difference in allelic expression of the CLCN1 gene and the possible influence on the myotonia congenita phenotype. | Dunø M | European journal of human genetics : EJHG | 2004 | PMID: 15162127 |
Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia. | Sun C | European journal of human genetics : EJHG | 2001 | PMID: 11840191 |
Founder mutations and the high prevalence of myotonia congenita in northern Finland. | Papponen H | Neurology | 1999 | PMID: 10430417 |
Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with various modes of inheritance including incomplete dominance and penetrance. | Plassart-Schiess E | Neurology | 1998 | PMID: 9566422 |
Mutations in the human skeletal muscle chloride channel gene (CLCN1) associated with dominant and recessive myotonia congenita. | Zhang J | Neurology | 1996 | PMID: 8857733 |
Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. | Koty PP | Neurology | 1996 | PMID: 8857727 |
Novel muscle chloride channel mutations and their effects on heterozygous carriers. | Mailänder V | American journal of human genetics | 1996 | PMID: 8571958 |
click to load more click to collapse |
Text-mined citations for rs80356704 ...
HelpRecord last updated Mar 11, 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.