rs150885084

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_000083.3(CLCN1):c.854G>A(p.Gly285Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G285R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense, splice_region

Scores

Splicing: ADA: 0.9909

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.99

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 13 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000083.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143324492-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2953283.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 7-143330772-G-A is Pathogenic according to our data. Variant chr7-143330772-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330772-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.854G>A	p.Gly285Glu	missense_variant, splice_region_variant	8/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.959G>A		splice_region_variant, non_coding_transcript_exon_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.854G>A	p.Gly285Glu	missense_variant, splice_region_variant	8/23	1	NM_000083.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152208

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251352

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74484

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000804

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2022	Observed in an affected mother and son with myotonia with presumed autosomal dominant inheritance (Thomas et al., 2008); Published functional studies demonstrate that the G285E variant leads to absent expression of chloride currents (Kubisch et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24037712, 15162127, 29606556, 18816629, 9736777, 11933197, 15786415, 18337730, 12390967, 29050397, 12210360, 22995991, 28662944, 12661046, 23810313, 31589614, 17932099, 34529042) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 18816629). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes loss of channel function as demonstrated by abrogation of chloride current (PMID 9736777). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 13, 2023	PP1, PP3, PM2, PM3, PS3, PS4_moderate -

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

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 16, 2021	The c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene substitutes a well conserved Glycine for Glutamic Acid at amino acid 285/989 (exon 8/23). This variant is found with low frequency in gnomAD(v3.1.1) (5 heterozygotes, 0 homozygotes; allele frequency: 3.29e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.93) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:280100) and has been identified in many affected individuals in the literature in homozygosity or compound heterozygosity with another variant [PMID:18337730; PMID: 24037712; others], and in some individuals with presumed autosomal recessive inheritance but without a second variant identified [PMID: 9736777; PMID:21387378; PMID: 24037712; others], as well as in one family with an affected mother and son and presumed autosomal dominant inheritance pattern [PMID:18816629]. Functional studies demonstrate the p.Gly285Glu variant leads to absence of chloride currents [PMID:9736777]. Given its identification in many affected individuals in the literature, functional studies showing deleterious effect, low frequency in population databases, and in silico algorithms prediction of a deleterious effect, the c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene is reported as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 285 of the CLCN1 protein (p.Gly285Glu). This variant is present in population databases (rs150885084, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 9736777, 12390967, 18337730, 21387378, 24037712). ClinVar contains an entry for this variant (Variation ID: 280100). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 9736777). For these reasons, this variant has been classified as Pathogenic. -

Smith-Lemli-Opitz syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 28, 2021

- -

Tip-toe gait

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Oct 10, 2022

- -

CLCN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

The CLCN1 c.854G>A variant is predicted to result in the amino acid substitution p.Gly285Glu. This variant has been reported in patients with autosomal recessive myotonia congenita (see, for example, Kubisch et al. 1998. PubMed ID: 9736777; Trip et al. 2008. PubMed ID: 18337730). In addition, it has been documented in the heterozygous state among several individuals with presumed autosomal recessive disease (Kubisch et al. 1998. PubMed ID: 9736777, Tan et al. 2014. PubMed ID: 24037712) and in at least one affected mother and her son with presumed autosomal dominant inheritance (Thomas et al. 2008. PubMed ID: 18816629). Functional studies on this variant have demonstrated that it affects chloride channel function (Kubisch et al. 1998. PubMed ID: 9736777). Of note, c.854G is the first base of exon eight and therefore this change may be more likely to impact splicing; however, visual inspection of splicing in silico predictions does not indicate a large impact (Alamut Visual Plus v1.6.1). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280100/). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic for autosomal recessive CLCN1-related disorders; however, it is uncertain in the context of an autosomal dominant mode of inheritance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.92

Polyphen

0.99

.;D

Vest4

0.99

MVP

0.99

MPC

0.84

ClinPred

0.94

GERP RS

4.6

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.19

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