NM_000083.3(CLCN1):c.1444G>A (p.Gly482Arg) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2024
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:: RCV000810078.7

Allele description [Variation Report for NM_000083.3(CLCN1):c.1444G>A (p.Gly482Arg)]

NM_000083.3(CLCN1):c.1444G>A (p.Gly482Arg)

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.1444G>A (p.Gly482Arg)

HGVS:

NC_000007.14:g.143339295G>A
NG_009815.2:g.28170G>A
NM_000083.3:c.1444G>AMANE SELECT
NP_000074.3:p.Gly482Arg
NC_000007.13:g.143036388G>A
NG_009815.1:g.28170G>A
NM_000083.2:c.1444G>A
NR_046453.2:n.1399G>A

Protein change:

G482R; GLY482ARG

Links:

OMIM: 118425.0005; dbSNP: rs746125212

NCBI 1000 Genomes Browser:

rs746125212

Molecular consequence:

NM_000083.3:c.1444G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1399G>A - 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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Gymnodoris striata voucher UF:IZ 368624 histone H3 (H3) gene, partial cds
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000950265	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 22346025, 25065301, 8533761, 15311340, 15786415, 31567646, 10644771, 17097617, 18035046, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000950265

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (10)
[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

Moroccan consanguineous family with Becker myotonia and review.

Ratbi I, Elalaoui SC, Escudero A, Kriouile Y, Molano J, Sefiani A.

Ann Indian Acad Neurol. 2011 Oct;14(4):307-9. doi: 10.4103/0972-2327.91963.

PubMed [citation]

PMID:: 22346025
PMCID:: PMC3271475

Effect of mexiletine on transitory depression of compound motor action potential in recessive myotonia congenita.

Lo Monaco M, D'Amico A, Luigetti M, Desaphy JF, Modoni A.

Clin Neurophysiol. 2015 Feb;126(2):399-403. doi: 10.1016/j.clinph.2014.06.008. Epub 2014 Jun 25.

PubMed [citation]

PMID:: 25065301

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000950265.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the CLCN1 protein (p.Gly482Arg). This variant is present in population databases (rs746125212, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22346025, 25065301; Invitae). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 8533761, 15311340, 15786415, 31567646); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 546108). 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: 10644771, 17097617, 18035046). 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

Last Updated: Oct 20, 2024

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