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NM_000083.3(CLCN1):c.652G>A (p.Ala218Thr) AND multiple conditions

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jan 13, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000803459.5

Allele description

NM_000083.3(CLCN1):c.652G>A (p.Ala218Thr)

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.652G>A (p.Ala218Thr)
HGVS:
  • NC_000007.14:g.143321804G>A
  • NG_009815.2:g.10679G>A
  • NM_000083.3:c.652G>AMANE SELECT
  • NP_000074.3:p.Ala218Thr
  • NC_000007.13:g.143018897G>A
  • NG_009815.1:g.10679G>A
  • NM_000083.2:c.652G>A
  • NR_046453.2:n.754G>A
Protein change:
A218T
Links:
dbSNP: rs189963844
NCBI 1000 Genomes Browser:
rs189963844
Molecular consequence:
  • NM_000083.3:c.652G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_046453.2:n.754G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000943331Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 13, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002799660Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Mar 17, 2022) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families.

de Diego C, Gámez J, Plassart-Schiess E, Lasa A, Del Río E, Cervera C, Baiget M, Gallano P, Fontaine B.

J Neurol. 1999 Sep;246(9):825-9.

PubMed [citation]
PMID:
10525982

Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene.

Mazón MJ, Barros F, De la Peña P, Quesada JF, Escudero A, Cobo AM, Pascual-Pascual SI, Gutiérrez-Rivas E, Guillén E, Arpa J, Eraso P, Portillo F, Molano J.

Neuromuscul Disord. 2012 Mar;22(3):231-43. doi: 10.1016/j.nmd.2011.10.013. Epub 2011 Nov 16.

PubMed [citation]
PMID:
22094069
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000943331.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 218 of the CLCN1 protein (p.Ala218Thr). This variant is present in population databases (rs189963844, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with myotonia congenita (PMID: 10525982). ClinVar contains an entry for this variant (Variation ID: 420147). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. This variant disrupts the p.Ala218 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 22094069), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV002799660.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 16, 2024