NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Jul 21, 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:: RCV000292791.42

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329301	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 21, 2024)	germline	clinical testing	Citation Link,
SCV000612784	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jul 5, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 22197187, 23097607, 8533761, 11840191, 18807109, 24349310, 17932099, 10644771, 17107341, 15980168, 12390967, 15162127, 17990293, 7874130, 29606556, 34529042, 33263785, 32528171, 33013670, 26467025
SCV001248214	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV001447748	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001449784	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 12, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002023245	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002037342	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002038260	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV005197520	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	33	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Becker myotonia patient with compound heterozygosity for CLCN1 mutations and Prinzmetal angina pectoris.

Zielonka D, Jurkat-Rott K, Stachowiak P, Bryl A, Marcinkowski JT, Lehmann-Horn F.

Neuromuscul Disord. 2012 Apr;22(4):355-60. doi: 10.1016/j.nmd.2011.10.024. Epub 2011 Dec 23.

PubMed [citation]

PMID:: 22197187

ClC1 chloride channel in myotonic dystrophy type 2 and ClC1 splicing in vitro.

Ursu SF, Alekov A, Mao NH, Jurkat-Rott K.

Acta Myol. 2012 Oct;31(2):144-53.

PubMed [citation]

PMID:: 23097607
PMCID:: PMC3476861

See all PubMed Citations (21)

Details of each submission

From GeneDx, SCV000329301.9

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

Description

Published functional studies demonstrate a damaging effect; R894X destabilizes the protein, possibly leading to reduced expression, and greatly reduces chloride currents in vitro (PMID: 8533761, 17990293); Nonsense variant predicted to result in protein truncation, as the last 95 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 22995991, 8845168, 10665666, 27142102, 27614575, 30824560, 32670189, 31216405, 7874130, 20301529, 25508133, 23739125, 18337100, 12661046, 8857733, 23097607, 11840191, 27296017, 28039888, 29424939, 34426522, 34008892, 33013670, 17990293, 38374194, 9576553, 32528171, 34106991, 33263785, 34418069, 35026467, 34529042, 37273706, 36628841, 36796140, 8533761, 15162127, 22197187)

#	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, SCV000612784.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

This variant is expected to result in the loss of a functional protein. This variant is one of the most common pathogenic variants identified in myotonia congenita patients worldwide (PMID: 20301529, 11840191) and is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is reported in the literature to segregate recessively in most families; however, cases of dominant segregation are also reported (PMID: 20301529, 11840191, 15162127, 7874130). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8533761, 17107341). 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.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001248214.22

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	31	not provided	not provided	clinical testing	not provided

Description

CLCN1: PM3:Very Strong, PVS1:Moderate, PM2:Supporting, PS3:Supporting

#	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		31	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447748.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002023245.3

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037342.1

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

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV002038260.1

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

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197520.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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