NM_000083.3(CLCN1):c.2831dup (p.Gly945fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 27, 2022
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:: RCV000307053.8

Allele description [Variation Report for NM_000083.3(CLCN1):c.2831dup (p.Gly945fs)]

NM_000083.3(CLCN1):c.2831dup (p.Gly945fs)

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.2831dup (p.Gly945fs)

HGVS:

NC_000007.14:g.143351829dup
NG_009815.2:g.40704dup
NM_000083.3:c.2831dupMANE SELECT
NP_000074.3:p.Gly945fs
NC_000007.13:g.143048918_143048919insC
NC_000007.13:g.143048922dup
NG_009815.1:g.40704dup
NM_000083.2:c.2831dup
NM_000083.2:c.2831dupC
NR_046453.2:n.2786dup
p.Gly945Argfs*39

Protein change:

G945fs

Links:

dbSNP: rs755176513

NCBI 1000 Genomes Browser:

rs755176513

Molecular consequence:

NM_000083.3:c.2831dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_046453.2:n.2786dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000329933	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Oct 17, 2018)	germline	clinical testing	Citation Link,
SCV000612786	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 9, 2022)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18337100, 32466254, 26467025
SCV002019332	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 27, 2022)	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

SCV000329933

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Oct 17, 2018)

germline

clinical testing

Citation Link,

SCV000612786

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 9, 2022)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002019332

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 27, 2022)

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	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

Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians.

Dupré N, Chrestian N, Bouchard JP, Rossignol E, Brunet D, Sternberg D, Brais B, Mathieu J, Puymirat J.

Neuromuscul Disord. 2009 May;19(5):330-4. doi: 10.1016/j.nmd.2008.01.007. Epub 2008 Mar 11.

PubMed [citation]

PMID:: 18337100

Comprehensive Exonic Sequencing of Known Ataxia Genes in Episodic Ataxia.

Maksemous N, Sutherland HG, Smith RA, Haupt LM, Griffiths LR.

Biomedicines. 2020 May 25;8(5). doi:pii: E134. 10.3390/biomedicines8050134.

PubMed [citation]

PMID:: 32466254
PMCID:: PMC7277596

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000329933.6

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

Description

The c.2831dupC likely pathogenic variant in the CLCN1 gene has been reported previously as c.2828insC due to alternative nomenclature, in an individual with severe myotonia, tongue myotonia, and lid myotonia, who also harbored a second CLCN1 pathogenic variant, suggestive of autosomal recessive inheritance (Dupree et al., 2009). The duplication causes a frameshift starting with codon Glycine 945, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Gly945ArgfsX39. This likely pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 44 amino acid residues are replaced with 38 incorrect amino acid residues. The c.2831dupC variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

#	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

From Athena Diagnostics, SCV000612786.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is expected to result in a shift of the reading frame and a premature stop codon. Since this variant is located in the last exon of the gene, variant-containing transcripts likely escape nonsense-mediated decay. This variant has been reported in multiple families with autosomal recessive myotonia congenita in published literature and internal data (PMID: 18337100, Athena Diagnostics internal data). This variant is also referred to as 2828insC in published literature.

#	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, SCV002019332.3

#	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

Last Updated: Sep 29, 2024

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