NM_000083.3(CLCN1):c.1607T>C (p.Val536Ala) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 10, 2023
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:: RCV003786318.2

Allele description [Variation Report for NM_000083.3(CLCN1):c.1607T>C (p.Val536Ala)]

NM_000083.3(CLCN1):c.1607T>C (p.Val536Ala)

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.1607T>C (p.Val536Ala)

HGVS:

NC_000007.14:g.143341953T>C
NG_009815.2:g.30828T>C
NM_000083.3:c.1607T>CMANE SELECT
NP_000074.3:p.Val536Ala
NC_000007.13:g.143039046T>C
NR_046453.2:n.1562T>C

Protein change:

V536A

Molecular consequence:

NM_000083.3:c.1607T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1562T>C - 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
SCV004570546	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23152584, 29405036, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004570546

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 10, 2023)

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

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 (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004570546.1

#	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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 536 of the CLCN1 protein (p.Val536Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. 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 determined to be pathogenic (PMID: 23152584, 29405036; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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