NM_000083.3(CLCN1):c.2647C>A (p.Pro883Thr) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 28, 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:: RCV001213417.3

Allele description [Variation Report for NM_000083.3(CLCN1):c.2647C>A (p.Pro883Thr)]

NM_000083.3(CLCN1):c.2647C>A (p.Pro883Thr)

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.2647C>A (p.Pro883Thr)

HGVS:

NC_000007.14:g.143351645C>A
NG_009815.2:g.40520C>A
NM_000083.3:c.2647C>AMANE SELECT
NP_000074.3:p.Pro883Thr
NC_000007.13:g.143048738C>A
NC_000007.13:g.143048738C>A
NG_009815.1:g.40520C>A
NM_000083.2:c.2647C>A
NR_046453.2:n.2602C>A

Protein change:

P883T

Links:

dbSNP: rs764347321

NCBI 1000 Genomes Browser:

rs764347321

Molecular consequence:

NM_000083.3:c.2647C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.2602C>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

Recent activity

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RecName: Full=Serine/threonine-protein kinase Nek5; AltName: Full=Never in mitos...
RecName: Full=Serine/threonine-protein kinase Nek5; AltName: Full=Never in mitosis A-related kinase 5; Short=NimA-related protein kinase 5
gi|74758252|sp|Q6P3R8.1|NEK5_HUMAN

Protein
OMIM Links for Protein (Select 83627721) (0)
OMIM

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001385046	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17932099, 29935101, 34529042, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001385046

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 28, 2023)

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

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

The analysis of myotonia congenita mutations discloses functional clusters of amino acids within the CBS2 domain and the C-terminal peptide of the ClC-1 channel.

Altamura C, Lucchiari S, Sahbani D, Ulzi G, Comi GP, D'Ambrosio P, Petillo R, Politano L, Vercelli L, Mongini T, Dotti MT, Cardani R, Meola G, Lo Monaco M, Matthews E, Hanna MG, Carratù MR, Conte D, Imbrici P, Desaphy JF.

Hum Mutat. 2018 Sep;39(9):1273-1283. doi: 10.1002/humu.23581. Epub 2018 Jul 4.

PubMed [citation]

PMID:: 29935101

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001385046.2

#	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 proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 883 of the CLCN1 protein (p.Pro883Thr). This variant is present in population databases (rs764347321, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of myotonia congenita (PMID: 17932099, 29935101, 34529042). ClinVar contains an entry for this variant (Variation ID: 943263). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 29935101, 34529042). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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