NM_000083.3(CLCN1):c.870C>G (p.Ile290Met) AND Congenital myotonia, autosomal recessive form

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 26, 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:: RCV001196224.4

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

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Kaposi's sarcoma-associated herpes-like virus polyadenylated nuclear transcript sequence
gi|1628554|gb|U50139.1|KSU50139

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001366774	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005204483	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 26, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8857727, 7581380 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001366774

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 1, 2016)

unknown

clinical testing

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

SCV005204483

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 26, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect.

Koty PP, Pegoraro E, Hobson G, Marks HG, Turel A, Flagler D, Cadaldini M, Angelini C, Hoffman EP.

Neurology. 1996 Oct;47(4):963-8.

PubMed [citation]

PMID:: 8857727

See all PubMed Citations (3)

Details of each submission

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366774.2

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

Description

This variant was classified as: Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005204483.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CLCN1 c.870C>G (p.Ile290Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.870C>G has been reported in the literature in nine heterozygous individuals in two families affected with Myotonia congenita and this variant show segregation with disease (Lehmann-Horn_1995, Koty_1996). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8857727, 7581380). ClinVar contains an entry for this variant (Variation ID: 17539). Based on the evidence outlined above, the variant was 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 13, 2024

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