ClinVar Genomic variation as it relates to human health
NM_000083.3(CLCN1):c.568G>A (p.Gly190Arg)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000083.3(CLCN1):c.568G>A (p.Gly190Arg)
Variation ID: 289004 Accession: VCV000289004.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 143321720 (GRCh38) [ NCBI UCSC ] 7: 143018813 (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 Oct 10, 2018 Jun 17, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000083.3:c.568G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000074.3:p.Gly190Arg missense NR_046453.2:n.670G>A non-coding transcript variant NC_000007.14:g.143321720G>A NC_000007.13:g.143018813G>A NG_009815.2:g.10595G>A - Protein change
- G190R
- Other names
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- Canonical SPDI
- NC_000007.14:143321719:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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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CLCN1 | - | - |
GRCh38 GRCh37 |
1369 | 1517 |
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
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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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Jan 11, 2024 | RCV000530513.8 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Apr 20, 2021 | RCV000711236.34 |
Submissions - Germline
Classification
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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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Uncertain significance
(Jun 27, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000343271.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(Sep 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000841568.3
First in ClinVar: Oct 20, 2018 Last updated: Jan 26, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. … (more)
The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Likely pathogenic
(Apr 20, 2021)
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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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GeneDx
Accession: SCV001822902.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22987687, 32670189, 23810313, 24037712, 24349310, 29606556) (less)
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Likely pathogenic
(May 28, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002022569.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000636298.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 190 of the CLCN1 protein (p.Gly190Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 190 of the CLCN1 protein (p.Gly190Arg). This variant is present in population databases (rs369773321, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 23810313, 24037712, 24349310). ClinVar contains an entry for this variant (Variation ID: 289004). 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%. This variant disrupts the p.Gly190 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19697366, 22921319, 23933576). 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. (less)
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Pathogenic
(Apr 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248202.22
First in ClinVar: May 12, 2020 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 1
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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 |
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Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. | Stunnenberg BC | Neuromuscular disorders : NMD | 2018 | PMID: 29606556 |
Chloride channels in myotonia congenita assessed by velocity recovery cycles. | Tan SV | Muscle & nerve | 2014 | PMID: 24037712 |
CLCN1 mutations in Czech patients with myotonia congenita, in silico analysis of novel and known mutations in the human dimeric skeletal muscle chloride channel. | Skálová D | PloS one | 2013 | PMID: 24349310 |
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 |
Muscle MRI reveals distinct abnormalities in genetically proven non-dystrophic myotonias. | Morrow JM | Neuromuscular disorders : NMD | 2013 | PMID: 23810313 |
Stiffness as a presenting symptom of an odd clinical condition caused by multiple sclerosis and myotonia congenita. | Portaro S | Neuromuscular disorders : NMD | 2013 | PMID: 22921319 |
A quantitative measure of handgrip myotonia in non-dystrophic myotonia. | Statland JM | Muscle & nerve | 2012 | PMID: 22987687 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CLCN1 | - | - | - | - |
Text-mined citations for rs369773321 ...
HelpRecord last updated Jun 17, 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.