NM_000083.3(CLCN1):c.870C>G (p.Ile290Met) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000690053.5

Allele description [Variation Report for NM_000083.3(CLCN1):c.870C>G (p.Ile290Met)]

NM_000083.3(CLCN1):c.870C>G (p.Ile290Met)

Gene:

CLCN1:chloride voltage-gated channel 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_000083.3(CLCN1):c.870C>G (p.Ile290Met)

HGVS:

NC_000007.14:g.143330788C>G
NG_009815.2:g.19663C>G
NM_000083.3:c.870C>GMANE SELECT
NP_000074.3:p.Ile290Met
NC_000007.13:g.143027881C>G
NG_009815.1:g.19663C>G
NM_000083.2:c.870C>G
NR_046453.2:n.975C>G
P35523:p.Ile290Met

Protein change:

I290M; ILE290MET

Links:

UniProtKB: P35523#VAR_001595; OMIM: 118425.0008; dbSNP: rs80356690

NCBI 1000 Genomes Browser:

rs80356690

Molecular consequence:

NM_000083.3:c.870C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.975C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: Myotonia congenita autosomal recessive; Becker disease; Myotonia generalized; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009715; MedGen: C0751360; Orphanet: 614; OMIM: 255700

Name:: Congenital myotonia, autosomal dominant form (THD)
Synonyms:: Myotonia congenita autosomal dominant; Thomsen disease; Thomsen's disease
Identifiers:: MONDO: MONDO:0008055; MedGen: C2936781; Orphanet: 614; OMIM: 160800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000817730	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 5, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10051520, 10962018, 758138, 12390967, 25036107, 23739125, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000817730

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 5, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

The muscle chloride channel ClC-1 has a double-barreled appearance that is differentially affected in dominant and recessive myotonia.

Saviane C, Conti F, Pusch M.

J Gen Physiol. 1999 Mar;113(3):457-68.

PubMed [citation]

PMID:: 10051520
PMCID:: PMC2222904

Fast and slow gating relaxations in the muscle chloride channel CLC-1.

Accardi A, Pusch M.

J Gen Physiol. 2000 Sep;116(3):433-44.

PubMed [citation]

PMID:: 10962018
PMCID:: PMC2233683

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000817730.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10051520, 10962018). 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. ClinVar contains an entry for this variant (Variation ID: 17539). This missense change has been observed in individuals with autosomal dominant congenital myotonia (PMID: 758138, 12390967, 23739125, 25036107). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive congenital myotonia (PMID: 23739125); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 290 of the CLCN1 protein (p.Ile290Met).

#	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

Last Updated: Oct 13, 2024

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