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NM_000083.3(CLCN1):c.895G>C (p.Val299Leu) AND Congenital myotonia, autosomal dominant form

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
May 4, 2022
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:
RCV002227481.2

Allele description [Variation Report for NM_000083.3(CLCN1):c.895G>C (p.Val299Leu)]

NM_000083.3(CLCN1):c.895G>C (p.Val299Leu)

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.895G>C (p.Val299Leu)
Other names:
NM_000083.3(CLCN1):c.895G>C
HGVS:
  • NC_000007.14:g.143330813G>C
  • NG_009815.2:g.19688G>C
  • NM_000083.3:c.895G>CMANE SELECT
  • NP_000074.3:p.Val299Leu
  • NC_000007.13:g.143027906G>C
  • NG_009815.1:g.19688G>C
  • NM_000083.2:c.895G>C
  • NR_046453.2:n.1000G>C
Protein change:
V299L
Links:
dbSNP: rs202179484
NCBI 1000 Genomes Browser:
rs202179484
Molecular consequence:
  • NM_000083.3:c.895G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_046453.2:n.1000G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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
SCV002507086Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(May 4, 2022) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002507086.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The heterozygous p.Val299Leu variant in CLCN1 was identified by our study in 1 individual with autosomal dominant myotonia congenita. The variant has been reported in 2 Dutch individuals with autosomal dominant myotonia congenita (PMID: 29606556), and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202179484). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 447073) as likely pathogenic by Athena Diagnostics Inc, and as having uncertain significance by GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting, PP3 (Richards 2015).

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

Last Updated: Sep 29, 2024