NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter) AND multiple conditions

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 31, 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:: RCV000627759.12

Allele description [Variation Report for NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)]

NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)

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.2680C>T (p.Arg894Ter)

HGVS:

NC_000007.14:g.143351678C>T
NG_009815.2:g.40553C>T
NM_000083.3:c.2680C>TMANE SELECT
NP_000074.3:p.Arg894Ter
NC_000007.13:g.143048771C>T
NG_009815.1:g.40553C>T
NM_000083.2:c.2680C>T
NR_046453.2:n.2635C>T
p.Arg894*
p.Arg894X

Protein change:

R894*; ARG894TER

Links:

OMIM: 118425.0015; dbSNP: rs55960271

NCBI 1000 Genomes Browser:

rs55960271

Molecular consequence:

NR_046453.2:n.2635C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000083.3:c.2680C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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

Recent activity

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Homo sapiens hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12), mRNA
Homo sapiens hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12), mRNA
gi|7705854|ref|NM_016142.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000636295	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 7874130, 8845168, 11840191, 15162127, 18337730, 22094069, 22197187, 24349310, 26096614, 27142102, 27296017, 27614575, 8533761, 17990293, 28492532
SCV000992751	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 17, 2012)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7874130, 22995991, 8533761, 27296017, 17990293, 10665666, 27614575, 23097607, 22197187, 25741868
SCV005038728	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (2) [See all records that cite these PMIDs] 7874130, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000636295

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV000992751

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 17, 2012)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV005038728

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

research

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
not provided	germline	yes	6	6	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC-1 chloride channel.

Pusch M, Steinmeyer K, Koch MC, Jentsch TJ.

Neuron. 1995 Dec;15(6):1455-63.

PubMed [citation]

PMID:: 8845168

Spectrum of CLCN1 mutations in patients with myotonia congenita in Northern Scandinavia.

Sun C, Tranebjaerg L, Torbergsen T, Holmgren G, Van Ghelue M.

Eur J Hum Genet. 2001 Dec;9(12):903-9. Erratum in: Eur J Hum Genet. 2010 Feb;18(2):264.

PubMed [citation]

PMID:: 11840191

See all PubMed Citations (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000636295.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This sequence change creates a premature translational stop signal (p.Arg894*) in the CLCN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the CLCN1 protein. This variant is present in population databases (rs55960271, gnomAD 1.7%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 7874130, 8533761, 8845168, 11840191, 15162127, 18337730, 22094069, 22197187, 24349310, 26096614, 27142102, 27296017, 27614575). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17545). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLCN1 function (PMID: 8533761, 17990293). 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 Baylor Genetics, SCV000992751.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	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 Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences, SCV005038728.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	research	PubMed (2)

Description

The c.2680C>T (p.(Arg894*)) variant was found in a heterozygous state in 6 Slovak patient with Myotonia congenita, 3 of whom carried also another Likely pathogenic variants in heterozygous state, namely c.1437_1450del, c.1238T>G, and c.1231G>T. The c.2680C>T variant is listed as a disease-causing in the HGMD database (CM940286) and it has been published for the first time in PMID: 7874130. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.0000315.

#	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		6	not provided	6	not provided

Last Updated: Oct 20, 2024

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