NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 5, 2023
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:: RCV000224894.42

Allele description [Variation Report for NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr)]

NM_000083.3(CLCN1):c.937G>A (p.Ala313Thr)

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.937G>A (p.Ala313Thr)

HGVS:

NC_000007.14:g.143330855G>A
NG_009815.2:g.19730G>A
NM_000083.3:c.937G>AMANE SELECT
NP_000074.3:p.Ala313Thr
NC_000007.13:g.143027948G>A
NG_009815.1:g.19730G>A
NM_000083.2:c.937G>A
NR_046453.2:n.1042G>A
P35523:p.Ala313Thr

Protein change:

A313T

Links:

UniProtKB: P35523#VAR_001599; dbSNP: rs80356692

NCBI 1000 Genomes Browser:

rs80356692

Molecular consequence:

NM_000083.3:c.937G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_046453.2:n.1042G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000281046	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 9, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000612807	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (May 5, 2023)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 31970219, 35170402, 24037712, 23893571, 23113340, 11840191, 19697366, 10533075, 18816629, 24349310, 28427807, 10619717, 29606556, 17042925, 11408615, 17654559, 17932099, 9566422, 9736777, 26467025
SCV001248205	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Sep 1, 2020)	germline	clinical testing	Citation Link,
SCV001872690	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 13, 2021)	germline	clinical testing	Citation Link,
SCV002017364	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 23, 2019)	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	4	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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

"Twitching" and Stiffness in POLG1 Mutation Carriers: Red Flag or Red Herring?

Pauly MG, Tunc S, Bäumer T, Gillessen-Kaesbach G, Münchau A.

Mov Disord Clin Pract. 2020 Jan;7(1):91-93. doi: 10.1002/mdc3.12860. No abstract available.

PubMed [citation]

PMID:: 31970219
PMCID:: PMC6962667

Clinical and molecular characteristics of myotonia congenita in China: Case series and a literature review.

Li Y, Li M, Wang Z, Yang F, Wang H, Bai X, Sun B, Chen S, Huang X.

Channels (Austin). 2022 Dec;16(1):35-46. doi: 10.1080/19336950.2022.2041292. Review.

PubMed [citation]

PMID:: 35170402
PMCID:: PMC8855856

See all PubMed Citations (21)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000281046.1

#	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	not provided	not provided	not provided	not provided		not provided	0.000371	not provided	not provided

From Athena Diagnostics, SCV000612807.6

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

Description

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is associated with autosomal dominant myotonia congenita in most families (PMID: 9566422, 17932099, 23893571, 24037712,31970219), however, it has been associated with autosomal recessive myotonia congenita in at least one family (PMID: 9566422, 23893571). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to decrease in current at physiologic voltages due to a positive shift in the voltage dependence of activation (PMID: 9736777, 17042925, 11408615).

#	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, SCV001248205.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	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		4	not provided	not provided	not provided

From GeneDx, SCV001872690.1

#	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 resulting in a positive voltage shift that creates a dominant negative effect on wild type channels and decrease in maximal amplitude (Kubisch et al., 1998; Tan et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9736777, 23893571, 31589614, 29896741, 27535533, 32670189, 28427807, 9566422, 23820649, 12163078, 24037712, 12566541, 15786415, 17042925, 16786525, 15389891, 10533075, 17654559, 24349310, 17932099, 23113340, 19697366, 11408615, 11933197, 23225051)

#	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 Revvity Omics, Revvity, SCV002017364.3

#	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: Oct 26, 2024

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