NM_000083.3(CLCN1):c.1781G>T (p.Gly594Val) AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 24, 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:: RCV001366416.4

Allele description [Variation Report for NM_000083.3(CLCN1):c.1781G>T (p.Gly594Val)]

NM_000083.3(CLCN1):c.1781G>T (p.Gly594Val)

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.1781G>T (p.Gly594Val)

HGVS:

NC_000007.14:g.143342127G>T
NG_009815.2:g.31002G>T
NM_000083.3:c.1781G>TMANE SELECT
NP_000074.3:p.Gly594Val
NC_000007.13:g.143039220G>T
NG_009815.1:g.31002G>T
NM_000083.2:c.1781G>T
NR_046453.2:n.1736G>T

Protein change:

G594V

Links:

dbSNP: rs746346988

NCBI 1000 Genomes Browser:

rs746346988

Molecular consequence:

NM_000083.3:c.1781G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1736G>T - 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
SCV001562717	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002075160	GenomeConnect, ClinGen	no classification provided	not provided	maternal	phenotyping only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001562717

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 24, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002075160

GenomeConnect, ClinGen

no classification provided

not provided

maternal

phenotyping only

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
not provided	maternal	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001562717.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 594 of the CLCN1 protein (p.Gly594Val). This variant is present in population databases (rs746346988, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 359112). 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

From GenomeConnect, ClinGen, SCV002075160.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Uncertain significance and reported on 11-09-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	unknown	not provided	not provided	validation		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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