rs80356703

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000083.3(CLCN1):c.1013G>A(p.Arg338Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.11

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 12 ACMG points.

PM1

In a topological_domain Extracellular (size 25) in uniprot entity CLCN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 7-143331265-G-A is Pathogenic according to our data. Variant chr7-143331265-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143331265-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	9/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.1118G>A		non_coding_transcript_exon_variant	9/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	9/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*298G>A		3_prime_UTR_variant, NMD_transcript_variant	9/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	9/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251482

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1461504

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2022	Published functional studies demonstrate the variant impairs normal muscle excitability (Zhang et al., 2000); 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: 15786415, 34426522, 7874130, 22187529, 11933197, 11840191, 31589614, 10690989, 10619717, 23739125, 18337100, 8533761, 18263754, 15311340, 18816629, 22521272, 29606556, 12390967, 32010054, 27415035, 8857733, 33263785) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant has been reported in multiple individuals with a single recessive pathogenic variant in the same gene, suggesting it is associated with autosomal recessive myotonia congenita (PMID: 18337100, 27415035, 33263785, 7874130), however, it has also been reported in a family with possible autosomal dominant myotonia congenita (PMID: 8857733). Assessment of experimental evidence suggests this variant results in abnormal protein function. The mutant protein caused a right-shift in the voltage-dependent of channel activation (PMID: 10690989). -

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

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 338 of the CLCN1 protein (p.Arg338Gln). This variant is present in population databases (rs80356703, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 7874130, 8857733, 12390967, 18337100, 23739125, 27415035; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21037). 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) has been performed at Invitae 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: 10690989). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

CLCN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been reported in the compound heterozygous state in individuals affected with autosomal recessive myotonia congenita (PMID: 7874130, 27415035) and also in individuals with autosomal dominant myotonia congenita (PMID: 8857733, 23739125). This variant has been described to show variable modes of transmission in different families including incomplete dominance and incomplete penetrance (20301529, 8857733, 12390967, 18337100). Functional studies in cultured muscle cells have shown that this missense change alters the properties of the CLCN1 chloride channel, which is thought to affect its ability to maintain normal muscle excitability (PMID: 10690989). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/282872) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1013G>A (p.Arg338Gln) variant is classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jun 05, 2023

Criteria applied: PS3,PM1,PM3,PS4_SUP,PP4 -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The CLCN1 c.1013G>A (p.Arg338Gln) variant has been reported with a second CLCN1 variant in individuals affected with autosomal recessive myotonia congenita (Yang X et al., 2016). Experimental studies has shown that this missense change alters the properties of the CLCN1 chloride channel in cell culture (Zhang J et al). This variant is reported with the allele frequency (0.0028%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Arg at position 338 is changed to a Gln changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg338Gln in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.86

Sift

Benign

0.14

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.88

MutPred

0.66

Loss of methylation at R338 (P = 0.0281);

MVP

0.95

MPC

0.74

ClinPred

0.93

GERP RS

4.9

Varity_R

0.60

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: -33

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