NM_000083.3(CLCN1):c.1667T>A (p.Ile556Asn) AND Congenital myotonia, autosomal recessive form

Germline classification:: Likely pathogenic (2 submissions)
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:: RCV001826481.13

Allele description [Variation Report for NM_000083.3(CLCN1):c.1667T>A (p.Ile556Asn)]

NM_000083.3(CLCN1):c.1667T>A (p.Ile556Asn)

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.1667T>A (p.Ile556Asn)

HGVS:

NC_000007.14:g.143342013T>A
NG_009815.2:g.30888T>A
NM_000083.3:c.1667T>AMANE SELECT
NP_000074.3:p.Ile556Asn
NC_000007.13:g.143039106T>A
NG_009815.1:g.30888T>A
NM_000083.2:c.1667T>A
NR_046453.2:n.1622T>A
P35523:p.Ile556Asn

Protein change:

I556N

Links:

UniProtKB: P35523#VAR_001612; dbSNP: rs80356697

NCBI 1000 Genomes Browser:

rs80356697

Molecular consequence:

NM_000083.3:c.1667T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1622T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

probably has functional consequence

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002075283	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19882638, 25741868
SCV004101540	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002075283

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

SCV004101540

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Homozygosity for dominant mutations increases severity of muscle channelopathies.

Arzel-Hézode M, Sternberg D, Tabti N, Vicart S, Goizet C, Eymard B, Fontaine B, Fournier E.

Muscle Nerve. 2010 Apr;41(4):470-7. doi: 10.1002/mus.21520.

PubMed [citation]

PMID:: 19882638

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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002075283.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101540.1

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

Description

The amino acid Ile at position 556 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Likely Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile556Asn in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change replaces isoleucine with asparagine at codon 556 of the CLCN1 protein (p.Ile556Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is present in population databases (rs80356697, ExAC 0.01%). This variant has been observed in the homozygous state in individuals affected with myotonia congenita as well as in the heterozygous state in more mildly affected and clinically unaffected individuals (Plassart-Schiess E et al, Arzel-Hézode M et al).This variant has been reported to affect CLCN1 protein function (Saviane C et al, Kubisch C et al). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 13, 2024

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