NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr) AND multiple conditions

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 20, 2023
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:: RCV000638231.17

Allele description [Variation Report for NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr)]

NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr)

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.937G>A (p.Ala313Thr)

HGVS:

NC_000007.14:g.143330855G>A
NG_009815.2:g.19730G>A
NM_000083.3:c.937G>AMANE SELECT
NP_000074.3:p.Ala313Thr
NC_000007.13:g.143027948G>A
NG_009815.1:g.19730G>A
NM_000083.2:c.937G>A
NR_046453.2:n.1042G>A
P35523:p.Ala313Thr

Protein change:

A313T

Links:

UniProtKB: P35523#VAR_001599; dbSNP: rs80356692

NCBI 1000 Genomes Browser:

rs80356692

Molecular consequence:

NM_000083.3:c.937G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1042G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000759717	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17654559, 17932099, 23225051, 23893571, 9736777, 28492532
SCV002810208	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2022)	unknown	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

SCV000759717

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 20, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002810208

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 8, 2022)

unknown

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

Citations

PubMed

Comparative efficacy of repetitive nerve stimulation, exercise, and cold in differentiating myotonic disorders.

Michel P, Sternberg D, Jeannet PY, Dunand M, Thonney F, Kress W, Fontaine B, Fournier E, Kuntzer T.

Muscle Nerve. 2007 Nov;36(5):643-50.

PubMed [citation]

PMID:: 17654559

Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions.

Fialho D, Schorge S, Pucovska U, Davies NP, Labrum R, Haworth A, Stanley E, Sud R, Wakeling W, Davis MB, Kullmann DM, Hanna MG.

Brain. 2007 Dec;130(Pt 12):3265-74. Epub 2007 Oct 11.

PubMed [citation]

PMID:: 17932099

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000759717.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 313 of the CLCN1 protein (p.Ala313Thr). This variant is present in population databases (rs80356692, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive myotonia congenita (PMID: 17654559, 17932099, 23225051, 23893571). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1024G>A. ClinVar contains an entry for this variant (Variation ID: 21052). 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: 9736777). 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

From Fulgent Genetics, Fulgent Genetics, SCV002810208.1

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

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

Last Updated: Oct 20, 2024

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