NM_000083.3(CLCN1):c.1606G>A (p.Val536Ile) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 30, 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:: RCV001049002.6

Allele description [Variation Report for NM_000083.3(CLCN1):c.1606G>A (p.Val536Ile)]

NM_000083.3(CLCN1):c.1606G>A (p.Val536Ile)

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.1606G>A (p.Val536Ile)

HGVS:

NC_000007.14:g.143341952G>A
NG_009815.2:g.30827G>A
NM_000083.3:c.1606G>AMANE SELECT
NP_000074.3:p.Val536Ile
NC_000007.13:g.143039045G>A
NG_009815.1:g.30827G>A
NM_000083.2:c.1606G>A
NR_046453.2:n.1561G>A

Protein change:

V536I

Links:

dbSNP: rs777685454

NCBI 1000 Genomes Browser:

rs777685454

Molecular consequence:

NM_000083.3:c.1606G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1561G>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
SCV001213034	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23152584, 29405036, 24304580, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001213034

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (4)
[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

New immunohistochemical method for improved myotonia and chloride channel mutation diagnostics.

Raheem O, Penttilä S, Suominen T, Kaakinen M, Burge J, Haworth A, Sud R, Schorge S, Haapasalo H, Sandell S, Metsikkö K, Hanna M, Udd B.

Neurology. 2012 Nov 27;79(22):2194-200. doi: 10.1212/WNL.0b013e31827595e2. Epub 2012 Nov 14.

PubMed [citation]

PMID:: 23152584
PMCID:: PMC3570820

Structural modeling of altered CLCN1 conformation following a novel mutation in a patient affected by autosomal dominant myotonia congenita (Thomsen disease).

Ferese R, Albano V, Falconi M, Iacovelli F, Campopiano R, Scala S, Griguoli AM, Gaglione A, Giardina E, Zampatti S, Storto M, Fornai F, D'Alessio C, Novelli G, Gambardella S.

Arch Ital Biol. 2017 Dec 1;155(4):118-130. doi: 10.12871/000398292017410. No abstract available.

PubMed [citation]

PMID:: 29405036

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213034.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 536 of the CLCN1 protein (p.Val536Ile). This variant is present in population databases (rs777685454, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita and late onset myotonia (PMID: 23152584, 29405036; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447054). 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%. This variant disrupts the p.Val536 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 24304580), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Sep 29, 2024

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