rs121912807

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.1495G>A(p.Gly499Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

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 topological_domain Extracellular (size 22) in uniprot entity CLCN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 7-143339534-G-A is Pathogenic according to our data. Variant chr7-143339534-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143339534-G-A is described in Lovd as [Pathogenic]. Variant chr7-143339534-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.1495G>A	p.Gly499Arg	missense_variant	Exon 14 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1450G>A		non_coding_transcript_exon_variant	Exon 13 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 link	c.1495G>A	p.Gly499Arg	missense_variant	Exon 14 of 23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 link	n.*780G>A		non_coding_transcript_exon_variant	Exon 14 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 link	n.*780G>A		3_prime_UTR_variant	Exon 14 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 link	c.1495G>A	p.Gly499Arg	missense_variant	Exon 14 of 23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727078

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myotonia, autosomal recessive form

Pathogenic:3

Feb 20, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

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.1495G>A (p.Gly499Arg) results in a non-conservative amino acid change in 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 4e-06 in 251464 control chromosomes. c.1495G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Myotonia congenita (Zhang_2000, Ivanova_2012, Ganapathy_2019, Marinakis_2024, Invitae). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in failed deactivation nor saturation of hyperpolarized channel protein and closure of mutant channels upon depolarization (Zhang_2000). The following publications have been ascertained in the context of this evaluation (PMID: 31069529, 23113340, 38855810, 10644771). ClinVar contains an entry for this variant (Variation ID: 17543). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 28, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 499 of the CLCN1 protein (p.Gly499Arg). This variant is present in population databases (rs121912807, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 10644771, 23113340; 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: 17543). 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. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10644771). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.99

MutPred

0.95

Loss of methylation at R496 (P = 0.0845);

MVP

0.97

MPC

0.81

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.26

Position offset: -4

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