NM_000083.3(CLCN1):c.1604C>T (p.Ala535Val) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 11, 2019
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:: RCV001059033.2

Allele description [Variation Report for NM_000083.3(CLCN1):c.1604C>T (p.Ala535Val)]

NM_000083.3(CLCN1):c.1604C>T (p.Ala535Val)

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.1604C>T (p.Ala535Val)

HGVS:

NC_000007.14:g.143341950C>T
NG_009815.2:g.30825C>T
NM_000083.3:c.1604C>TMANE SELECT
NP_000074.3:p.Ala535Val
NC_000007.13:g.143039043C>T
NG_009815.1:g.30825C>T
NM_000083.2:c.1604C>T
NR_046453.2:n.1559C>T

Protein change:

A535V

Links:

dbSNP: rs752814433

NCBI 1000 Genomes Browser:

rs752814433

Molecular consequence:

NM_000083.3:c.1604C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1559C>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
SCV001223637	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 11, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23739125, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001223637

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 11, 2019)

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

A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene.

Brugnoni R, Kapetis D, Imbrici P, Pessia M, Canioni E, Colleoni L, de Rosbo NK, Morandi L, Cudia P, Gashemi N, Bernasconi P, Desaphy JF, Conte D, Mantegazza R.

J Hum Genet. 2013 Sep;58(9):581-7. doi: 10.1038/jhg.2013.58. Epub 2013 Jun 6.

PubMed [citation]

PMID:: 23739125

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, SCV001223637.1

#	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 alanine with valine at codon 535 of the CLCN1 protein (p.Ala535Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLCN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala535 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 23739125), which suggests that this may be a clinically significant amino acid residue. 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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