NM_000083.3(CLCN1):c.895G>C (p.Val299Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 21, 2022
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:: RCV001851431.3

Allele description [Variation Report for NM_000083.3(CLCN1):c.895G>C (p.Val299Leu)]

NM_000083.3(CLCN1):c.895G>C (p.Val299Leu)

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.895G>C (p.Val299Leu)

Other names:

NM_000083.3(CLCN1):c.895G>C

HGVS:

NC_000007.14:g.143330813G>C
NG_009815.2:g.19688G>C
NM_000083.3:c.895G>CMANE SELECT
NP_000074.3:p.Val299Leu
NC_000007.13:g.143027906G>C
NG_009815.1:g.19688G>C
NM_000083.2:c.895G>C
NR_046453.2:n.1000G>C

Protein change:

V299L

Links:

dbSNP: rs202179484

NCBI 1000 Genomes Browser:

rs202179484

Molecular consequence:

NM_000083.3:c.895G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1000G>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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DNA methyltransferase [Homo sapiens]
DNA methyltransferase [Homo sapiens]
gi|2894544|emb|CAA11272.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002285750	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29606556, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002285750

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 21, 2022)

germline

clinical testing

PubMed (2)
[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

Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands.

Stunnenberg BC, Raaphorst J, Deenen JCW, Links TP, Wilde AA, Verbove DJ, Kamsteeg EJ, van den Wijngaard A, Faber CG, van der Wilt GJ, van Engelen BGM, Drost G, Ginjaar HB.

Neuromuscul Disord. 2018 May;28(5):402-407. doi: 10.1016/j.nmd.2018.03.006. Epub 2018 Mar 9.

PubMed [citation]

PMID:: 29606556

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002285750.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 299 of the CLCN1 protein (p.Val299Leu). This variant is present in population databases (rs202179484, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal dominant CLCN1-related conditions (PMID: 29606556). ClinVar contains an entry for this variant (Variation ID: 447073). 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. 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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