rs80356700

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.689G>A(p.Gly230Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:2

Conservation

PhyloP100: 8.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a transmembrane_region Helical (size 17) in uniprot entity CLCN1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 7-143321841-G-A is Pathogenic according to our data. Variant chr7-143321841-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143321841-G-A is described in Lovd as [Pathogenic]. Variant chr7-143321841-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.689G>A	p.Gly230Glu	missense_variant	5/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.791G>A		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.689G>A	p.Gly230Glu	missense_variant	5/23	1	NM_000083.3	ENSP00000339867	P4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

251000

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 09, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is associated with autosomal dominant myotonia congenita in most families (PMID: 10533075, 8857727, 7981750, 18220014, 10467912, 23516313), however, it has also been associated with autosomal recessive myotonia congenita (PMID: 8857733, 23516313). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9122265, 8112288) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 25, 2020	PS3, PS4, PP1, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	Reported previously in multiple unrelated families with myotonia congenita, most often in association with autosomal dominant inheritance (George et al., 1993; Meyer-Kleine et al., 1995).; Reported in a family exhibiting autosomal dominant inheritance, at least one carrier of G230E variant was reported to be clinically unaffected in adulthood, although EMG revealed subclinical myotonia (Meyer-Kleine et al., 1995).; Published functional studies have demonstrated that the Gly230 residue resides within the chloride channel pore and the G230E variant dramatically alters pore properties (Fahlke et al., 1997); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10467912, 10533075, 15786415, 23739125, 28427807, 7981750, 8857733, 10720929, 11933197, 12390967, 18220014, 24349310, 18263754, 19570891, 9122265, 8857727, 8533761, 20301529, 29424939, 29606556, 31692161, 32670189) -

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

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 230 of the CLCN1 protein (p.Gly230Glu). This variant is present in population databases (rs80356700, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant myotonia congenita (PMID: 7981750, 18220014). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly180Glu. ClinVar contains an entry for this variant (Variation ID: 17532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 8112288, 9122265). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 31, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 03-09-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Congenital myotonia, autosomal dominant form

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 18, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 12, 2021	The CLCN1 c.689G>A (p.Gly230Glu) variant is a missense variant. Across a selection of the available literature, the p.Gly230Glu variant has been identified in a heterozygous state in at least eight probands and 12 affected family members with autosomal dominant myotonia congenita from eight families showing segregation with the disorder (George et al. 1993; Koty et al. 1996; Brugnoni et al. 1999, Chang et al. 2015). Expressivity of the disease associated with the variant is variable, Chang et al. (2015) reported the variant to be present in a heterozygous state in one 17-year-old female asymptomatic carrier in a family with two affected individuals. The p.Gly230Glu variant was also reported in a compound heterozygous state with a stop gained variant in one individual, in whose family both the mother and sibling were noted to be carriers of the p.Gly230Glu variant and asymptomatic (Zhang et al. 1996). The p.Gly230Glu variant is reported at a frequency of 0.000012 in the total population of the Genome Aggregation Database (version 2.1.1) in a region of good sequence coverage. Heterologous expression of the p.Gly230Glu variant in Xenopus oocytes suggest the variant exerts a dominant negative effect on the channel. Additional work in mammalian cell lines showed that the p.Gly230Glu variant induced changes in ion selectivity relative to the wildtype protein (Steinmeyer et al. 1994; Fahlke et al. 1997). Based on the collective evidence and application of the ACMG criteria, the p.Gly230Glu variant is classified as pathogenic for the autosomal dominant form of myotonia congenita. -

CLCN1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

The CLCN1 c.689G>A variant is predicted to result in the amino acid substitution p.Gly230Glu. This variant has been previously reported in multiple families with myotonia congenita, primarily in association with autosomal dominant inheritance (George et al. 1993. PubMed ID: 7981750; Meyer-Kleine et al. 1995. PubMed ID: 8533761; Chang et al. 2007. PubMed ID: 18220014). Functional studies suggested that the p.Gly230Glu substitution dramatically altered the pore properties of CLCN1 (Fahlke et al. 1997. PMID: 9122265). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 27, 2023

Variant summary: CLCN1 c.689G>A (p.Gly230Glu) results in a non-conservative amino acid change located in the TM1 domain (Sutterlin_2022) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251000 control chromosomes. c.689G>A has been reported in the literature as a heterozygous genotype or as a compound heterozygous genotype in multiple individuals affected with Congenital Myotonia (example, Sutterlin_2022; Horga_2013). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Fahlke_1997, Steinmeyer_1994). The most pronounced variant effect results in altered pore properties of the muscle chloride channel (Fahle_1997) and destroy normal channel activity while exerting a dominant negative effect of wild-type channels (Steinmeyer_1994). The following publications have been ascertained in the context of this evaluation (PMID: 9122265, 23516313, 8112288, 34529042). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Batten-Turner congenital myopathy

Other:1

not provided, no classification provided

literature only

GeneReviews

Associated with autosomal recessive and autosomal dominant mode of inheritance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.4

.;H

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.8

.;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

.;D

Vest4

0.96

MVP

0.99

MPC

0.85

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over