NM_000083.3(CLCN1):c.434-2_434dup AND not provided

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Jun 22, 2025
Review status:: criteria provided, conflicting classifications

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:: RCV002473050.10

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002771104	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Apr 4, 2022)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31544778, 26467025
SCV003830732	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 22, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006308192	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Feb 12, 2025)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002771104

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Apr 4, 2022)

unknown

clinical testing

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

SCV003830732

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 22, 2025)

germline

clinical testing

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

SCV006308192

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Feb 12, 2025)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	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

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (3)

Details of each submission

From Athena Diagnostics, SCV002771104.1

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

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In our internal patient population, this variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. This variant has been seen heterozygous and compound heterozygous in at least one individual with clinical features associated with this gene. This variant is also referred to as c.434-5_434-4insGCA in published literature. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing.

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

From Revvity Omics, Revvity, SCV003830732.3

#	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

From GeneDx, SCV006308192.1

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

Description

Observed multiple times with a pathogenic variant in unrelated patients with myotonia congenita in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 34529042); Observed as heterozygous variant in one patient with muscular hypertrophy and warm-up phenomenon and also observed with a pathogenic variant in a patient with myotonic runs on EMG in published literature. It is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes. (PMID: 31544778); Canonical splice site variant with an unclear effect on protein function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.434-5insGCA; This variant is associated with the following publications: (PMID: 31544778, 34529042)

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

Last Updated: Sep 14, 2025

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