rs746125212

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.1444G>A(p.Gly482Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G482?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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 16 ACMG points.

PM1

In a transmembrane_region Helical (size 19) in uniprot entity CLCN1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143339295-G-M is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 7-143339295-G-A is Pathogenic according to our data. Variant chr7-143339295-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 546108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143339295-G-A is described in Lovd as [Pathogenic]. Variant chr7-143339295-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.1444G>A	p.Gly482Arg	missense_variant	13/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.1399G>A		non_coding_transcript_exon_variant	12/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1444G>A	p.Gly482Arg	missense_variant	13/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*729G>A		3_prime_UTR_variant, NMD_transcript_variant	13/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1444G>A	p.Gly482Arg	missense_variant	13/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460820

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

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	May 03, 2021	Observed in the heterozygous state, without a second pathogenic variant, in multiple individuals with Thomson disease (domiant form), although some individuals were reported to have clinical features consistent with the more severe Becker disease (recessive form) (Meyer-Kleine et al., 1995; Jou et al., 2004; Lo Monaco et al., 2004); Observed in the heterozygous state in a patient with myotonia congenita and was found to be inherited from an unaffected father (Jou et al., 2004); Observed in patients with myotonia congenita who harbored a second CLCN1 variant in the literature and referred for genetic testing at GeneDx (Lo Monaco et al., 2015); Published functional studies with electrophysiological analysis of Xenopus oocytes demonstrate G482R results in loss of CLCN1 channel function (Lin et al., 2006); Not observed at a 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: 23739125, 17097617, 10644771, 15311340, 24349310, 25065301, 28427807, 15786415, 12210360, 8533761, 31567646, 31544778, 22346025) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 29, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CLCN1: PS3, PS4, PM2, PM5, PP3, PS2:Supporting -

Congenital myotonia, autosomal recessive form

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	This sequence change in CLCN1 is predicted to replace glycine with arginine at codon 482, p.(Gly482Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is a critical glycine residue in the helical transmembrane M-N Linker domain of the chloride ion channel (PMID: 24349310). There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (2/16,256 alleles) in the African/African American population, which is consistent with a recessive disease. This variant has been detected in at least three individuals with autosomal recessive/Becker myotonia congenita (MC). Of those individuals, one individual was homozygous and two were compound heterozygous for the variant and a pathogenic variant, confirmed in trans (PMID: 22346025, 37066920; LOVD). The variant is reported to segregate with disease in the homozygous state in a single family (PMID: 22346025). There are limited reports of the variant in autosomal dominant/Thomsen MC (PMID: 15311340, 31567646). In vitro patch-clamp assays with limited validation in HEK293 cells and Xenopus oocytes demonstrate the variant leads to a loss of chloride channel function (PMID: 10644771, 17097617, 18035046). Computational evidence [predicts a deleterious effect/ predicts a benign effect/ is uninformative] for the missense substitution (REVEL = 0.997). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM1, PP3_Moderate, PM2_Supporting, PS3_Supporting, PP1. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 07, 2013	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the CLCN1 protein (p.Gly482Arg). This variant is present in population databases (rs746125212, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22346025, 25065301; Invitae). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 8533761, 15311340, 15786415, 31567646); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 546108). 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: 10644771, 17097617, 18035046). For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.98

Gain of methylation at G482 (P = 0.0278);

MVP

0.99

MPC

0.81

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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