rs146457619

Variant names:

• chr7-143339304-A-G
• rs146457619
• NM_000083.3:c.1453A>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM5 PP2 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1453A>G​(p.Met485Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,613,142 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M485K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.31
• Publications: 24 publications found

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CLCN1 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143339305-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2934639.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.
• PP5: Variant 7-143339304-A-G is Pathogenic according to our data. Variant chr7-143339304-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 280101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1453A>G	p.Met485Val	missense_variant	Exon 13 of 23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1408A>G		non_coding_transcript_exon_variant	Exon 12 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1453A>G	p.Met485Val	missense_variant	Exon 13 of 23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*738A>G		non_coding_transcript_exon_variant	Exon 13 of 23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*738A>G		3_prime_UTR_variant	Exon 13 of 23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1453A>G	p.Met485Val	missense_variant	Exon 13 of 23			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000398 AC: 100 AN: 251490 AF XY: 0.000419

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1460812 Hom.: 1 Cov.: 31 AF XY: 0.000590 AC XY: 429 AN XY: 726794

African (AFR) AF: 0.0000897 AC: 3 AN: 33454

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000762 AC: 847 AN: 1111018

Other (OTH) AF: 0.000497 AC: 30 AN: 60368

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74492

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000431

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Sep 24, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate variant leads to drastic reduction of single channel conductance, is strongly inwardly rectifying, and incompletely deactivates at negative voltages (Wollnik et al., 1997); This variant is associated with the following publications: (PMID: 23739125, 9736777, 32509969, 33464536, 33314145, 8533761, 25088311, 24920213, 22094069, 9158157, 28427807, 29606556, 17932099, 31544778, 32010054, 31589614) -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLCN1: PM3:Strong, PM5, PP1:Moderate, PM2:Supporting, PP3, PS3:Supporting -

Aug 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PM2, PM3_strong, PS3, PS4 -

Jan 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 has been identified in multiple individuals with recessive myotonia congenita (PMID: 8533761, 18337100, 22094069, 24349310, 24920213). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9158157, 34529042) -

Congenital myotonia, autosomal recessive form Pathogenic:3 Other:1

Nov 05, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in CLCN1 is predicted to replace methionine with valine at codon 485, p.(Met485Val). The methionine residue is highly conserved (100 vertebrates, UCSC), and is a critical methionine residue in the helical transmembrane M-N Linker domain of the chloride ion channel (PMID: 24349310). There is a small physicochemical difference between methionine and valine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.06% (84/129,188 alleles) in the European (non-Finnish) population. This variant has been detected in multiple individuals with autosomal recessive/Becker myotonia congenita in the homozygous and compound heterozygous state and segregates with recessive disease in at least one family (PMID: 8533761, 24920213, 31544778, 22094069). An in vitro patch-clamp assay with limited validation in Xenopus oocytes demonstrates the variant causes a loss of chloride channel function and no dominant negative effect (PMID: 9158157). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.774). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM1, PP1, PP3, PS3_Supporting. -

Sep 23, 2020

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 09-23-2020 by Lab or GTR ID New York Genome Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Sep 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLCN1 c.1453A>G (p.Met485Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251490 control chromosomes (gnomAD). c.1453A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with autosomal recessive Congenital Myotonia, including at least one case where it was confirmed to be in trans with a pathogenic variant and was found to segregate with the disease phenotype within members of the same family (e.g. Meyer-Kleine_1995, Suetterlin_2022). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating the variant in Xenopus oocytes and found that the variant severely impairs channel function, but does not exert a dominant negative effect when expressed with the wild type protein, consistent with it having an autosomal recessive mode of inheritance (e.g. Wollnik_1997, Suetterlin_2022). The following publications have been ascertained in the context of this evaluation (PMID: 8533761, 34529042, 9158157). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority of submitters classified the variant as pathogenic (n=6) and others classified it as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 485 of the CLCN1 protein (p.Met485Val). This variant is present in population databases (rs146457619, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8533761, 9736777, 17932099, 18337100, 22094069, 24037712, 24349310). 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. ClinVar contains an entry for this variant (Variation ID: 280101). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 9158157). For these reasons, this variant has been classified as Pathogenic. -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Batten-Turner congenital myopathy Pathogenic:1

Dec 18, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CLCN1 c.1453A>G (p.Met485Val) missense variant has been reported in at least six studies in which it is found in a total of 13 individuals with myotonia congenita, including two in a homozygous state, ten in a compound heterozygous state (including two siblings) and one proband with unspecified zygosity (Meyer-Kleine et al. 1995; Fialho et al. 2007; Mazon et al. 2012; Skálová et al. 2013; Brugnoni et al. 2013; Hoche et al. 2014). The variant has also been reported in a heterozygous state in at least three unaffected relatives (Meyer-Kleine et al. 1995; Hoche et al. 2014). The p.Met485Val variant was absent from 200 control alleles but is reported at a frequency of 0.000773 in the Other population of the Genome Aggregation Database. Functional studies involving expression in Xenopus oocytes demonstrated that the variant led to a drastic reduction of the single channel conductance compared to wildtype (Wollnik et al. 1997). Based on the evidence, the p.Met485Val variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

CLCN1-related disorder Pathogenic:1

May 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CLCN1 c.1453A>G variant is predicted to result in the amino acid substitution p.Met485Val. This variant has been reported in the homozygous and compound heterozgyous states in mutliple individuals with autosomal recessive myotonia congenita (Dupré et al. 2009. PubMed ID: 18337100; Mazón et al. 2012. PubMed ID: 22094069; Milla et al. 2019. PubMed ID: 31544778; Suetterlin et al. 2022. PubMed ID: 34529042) and has been observed to co-segregate with disease in at least one family (Meyer-Kleine et al. 1995. PubMed ID: 8533761). In vitro functional studies have demonstrated that this variant negatively impacts chloride channel function (Wollnik et al. 1997. PubMed ID: 9158157; Kubisch et al. 1998. PubMed ID: 9736777; Tan et al. 2013. PubMed ID: 24037712; Suetterlin et al. 2022. PubMed ID: 34529042). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, other missense variants at this amino acid residue (p.Met485Lys, p.Met485Glu) have been reported in individuals with CLCN1-related disease (Fialho et al. 2007. PubMed ID: 17932099; Suetterlin et al. 2022. PubMed ID: 34529042). Taken together, this variant is interpreted as pathogenic for autosomal recessive CLCN1-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.076	D
MutationAssessor	Benign	-0.060	N
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.77
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.75	P
Vest4		0.93
MVP		0.90
MPC		0.46
ClinPred		0.065	T
GERP RS		5.6
Varity_R		0.57
gMVP		0.87
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146457619; hg19: chr7-143036397;