NM_000083.3(CLCN1):c.1649C>G (p.Thr550Arg) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 9, 2024
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:: RCV003770636.3

Allele description [Variation Report for NM_000083.3(CLCN1):c.1649C>G (p.Thr550Arg)]

NM_000083.3(CLCN1):c.1649C>G (p.Thr550Arg)

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.1649C>G (p.Thr550Arg)

HGVS:

NC_000007.14:g.143341995C>G
NG_009815.2:g.30870C>G
NM_000083.3:c.1649C>GMANE SELECT
NP_000074.3:p.Thr550Arg
NC_000007.13:g.143039088C>G
NG_009815.1:g.30870C>G
NR_046453.2:n.1604C>G

Protein change:

T550R

Links:

dbSNP: rs762754992

NCBI 1000 Genomes Browser:

rs762754992

Molecular consequence:

NM_000083.3:c.1649C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1604C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: BECKER DISEASE; Becker Generalized Myotonia
Identifiers:: MONDO: MONDO:0009715; MedGen: C0751360; Orphanet: 614; OMIM: 255700

Name:: Congenital myotonia, autosomal dominant form (THD)
Synonyms:: THOMSEN DISEASE; Myotonia congenita autosomal dominant
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
SCV004569617	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21221019, 33263785, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004569617

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 9, 2024)

germline

clinical testing

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

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

Citations

PubMed

Low-rate repetitive nerve stimulation protocol in an Italian cohort of patients affected by recessive myotonia congenita.

Modoni A, D'Amico A, Dallapiccola B, Mereu ML, Merlini L, Pagliarani S, Pisaneschi E, Silvestri G, Torrente I, Valente EM, Lo Monaco M.

J Clin Neurophysiol. 2011 Feb;28(1):39-44. doi: 10.1097/WNP.0b013e31820510d7.

PubMed [citation]

PMID:: 21221019

Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients.

Vereb N, Montagnese F, Gläser D, Schoser B.

J Neurol. 2021 May;268(5):1708-1720. doi: 10.1007/s00415-020-10328-1. Epub 2020 Dec 2.

PubMed [citation]

PMID:: 33263785
PMCID:: PMC8068660

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004569617.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 550 of the CLCN1 protein (p.Thr550Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 21221019, 33263785). ClinVar contains an entry for this variant (Variation ID: 1013567). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 13, 2025

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