NM_000083.3(CLCN1):c.1261dup (p.Arg421fs) AND multiple conditions

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 28, 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:: RCV000691433.11

Allele description [Variation Report for NM_000083.3(CLCN1):c.1261dup (p.Arg421fs)]

NM_000083.3(CLCN1):c.1261dup (p.Arg421fs)

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.1261dup (p.Arg421fs)

HGVS:

NC_000007.14:g.143332733dup
NG_009815.1:g.21608dup
NM_000083.3:c.1261dupMANE SELECT
NP_000074.3:p.Arg421fs
NC_000007.13:g.143029822_143029823insC
NC_000007.13:g.143029826dup
NM_000083.2:c.1261dup
NM_000083.2:c.1261dupC
p.Arg421Profs*9

Protein change:

R421fs

Links:

dbSNP: rs763633152

NCBI 1000 Genomes Browser:

rs763633152

Molecular consequence:

NM_000083.3:c.1261dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000819211	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17932099, 22094069, 23739125, 8533761, 28492532
SCV002799217	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 28, 2022)	unknown	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

SCV000819211

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002799217

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 28, 2022)

unknown

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	unknown	unknown	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

Citations

PubMed

Chloride channel myotonia: exon 8 hot-spot for dominant-negative interactions.

Fialho D, Schorge S, Pucovska U, Davies NP, Labrum R, Haworth A, Stanley E, Sud R, Wakeling W, Davis MB, Kullmann DM, Hanna MG.

Brain. 2007 Dec;130(Pt 12):3265-74. Epub 2007 Oct 11.

PubMed [citation]

PMID:: 17932099

Screening for mutations in Spanish families with myotonia. Functional analysis of novel mutations in CLCN1 gene.

Mazón MJ, Barros F, De la Peña P, Quesada JF, Escudero A, Cobo AM, Pascual-Pascual SI, Gutiérrez-Rivas E, Guillén E, Arpa J, Eraso P, Portillo F, Molano J.

Neuromuscul Disord. 2012 Mar;22(3):231-43. doi: 10.1016/j.nmd.2011.10.013. Epub 2011 Nov 16.

PubMed [citation]

PMID:: 22094069

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819211.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Arg421Profs*9) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs763633152, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8533761). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 1262insC. ClinVar contains an entry for this variant (Variation ID: 447048). 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, SCV002799217.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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