NM_000083.3(CLCN1):c.434-2_434dup AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000550058.10

Allele description [Variation Report for NM_000083.3(CLCN1):c.434-2_434dup]

NM_000083.3(CLCN1):c.434-2_434dup

Gene:

CLCN1:chloride voltage-gated channel 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_000083.3(CLCN1):c.434-2_434dup

HGVS:

NC_000007.14:g.143321363_143321365dup
NG_009815.2:g.10238_10240dup
NM_000083.3:c.434-2_434dupMANE SELECT
NC_000007.13:g.143018453_143018454insGCA
NC_000007.13:g.143018456_143018458dup
NG_009815.1:g.10238_10240dup
NM_000083.2:c.434-2_434dup
NM_000083.2:c.434-2_434dupAGC
NM_000083.3:c.434-2_434dupAGCMANE SELECT
NM_000083.3:c.434_435insAGCMANE SELECT

Links:

dbSNP: rs753470655

NCBI 1000 Genomes Browser:

rs753470655

Molecular consequence:

NM_000083.3:c.434-2_434dup - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Congenital myotonia, autosomal recessive form
Synonyms:: BECKER DISEASE; Becker Generalized Myotonia
Identifiers:: MONDO: MONDO:0009715; MedGen: C0751360; Orphanet: 614; OMIM: 255700

Name:: Congenital myotonia, autosomal dominant form (THD)
Synonyms:: THOMSEN DISEASE; Myotonia congenita autosomal dominant
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
SCV000636331	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31544778, 28492532
SCV005667206	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 23, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000636331

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005667206

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 23, 2024)

germline

clinical testing

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

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

Myotonia congenita: mutation spectrum of CLCN1 in Spanish patients.

Milla CP, De Castro CP, Gómez-González C, Martínez-Montero P, Pascual Pascual SI, Molano Mateos J.

J Genet. 2019 Sep;98. doi:pii: 71.

PubMed [citation]

PMID:: 31544778

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000636331.8

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

Description

This variant, c.434-2_434dup, results in the insertion of 1 amino acid(s) of the CLCN1 protein (p.Ala145dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753470655, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of autosomal recessive myotonia congenita (PMID: 31544778; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 31544778); however, the role of the variant in this condition is currently unclear. This variant is also known as c.434-5_434-4insGCA. ClinVar contains an entry for this variant (Variation ID: 462844). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as 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

From Fulgent Genetics, Fulgent Genetics, SCV005667206.1

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

#	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 14, 2025

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