rs80356692

Positions:

chr7-143330855-G-A

Variant summary

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

The NM_000083.3(CLCN1):c.937G>A(p.Ala313Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,070 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

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 14 ACMG points.

PM1

In a transmembrane_region Helical (size 19) in uniprot entity CLCN1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 7-143330855-G-A is Pathogenic according to our data. Variant chr7-143330855-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330855-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.937G>A	p.Ala313Thr	missense_variant	8/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.1042G>A		non_coding_transcript_exon_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.937G>A	p.Ala313Thr	missense_variant	8/23	1	NM_000083.3	ENSP00000339867	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251428

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135878

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:

0.00000752

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727248

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

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	May 05, 2023	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is associated with autosomal dominant myotonia congenita in most families (PMID: 9566422, 17932099, 23893571, 24037712,31970219), however, it has been associated with autosomal recessive myotonia congenita in at least one family (PMID: 9566422, 23893571). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to decrease in current at physiologic voltages due to a positive shift in the voltage dependence of activation (PMID: 9736777, 17042925, 11408615). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2021	Published functional studies demonstrate a damaging effect resulting in a positive voltage shift that creates a dominant negative effect on wild type channels and decrease in maximal amplitude (Kubisch et al., 1998; Tan et al., 2014); Not observed at 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: 9736777, 23893571, 31589614, 29896741, 27535533, 32670189, 28427807, 9566422, 23820649, 12163078, 24037712, 12566541, 15786415, 17042925, 16786525, 15389891, 10533075, 17654559, 24349310, 17932099, 23113340, 19697366, 11408615, 11933197, 23225051) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 313 of the CLCN1 protein (p.Ala313Thr). This variant is present in population databases (rs80356692, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive myotonia congenita (PMID: 17654559, 17932099, 23225051, 23893571). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1024G>A. ClinVar contains an entry for this variant (Variation ID: 21052). 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: 9736777). For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 20, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Dec 06, 2022	ACMG Criteria: PS3, PM1, PM2_P, PM5, PP3, PP5; Variant was found in heterozygous state. -

Congenital myotonia, autosomal recessive form

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

.;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.7

.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

.;D

Vest4

0.87

MutPred

0.88

Loss of stability (P = 0.091);Loss of stability (P = 0.091);

MVP

0.98

MPC

0.73

ClinPred

0.99

GERP RS

4.6

Varity_R

0.92

gMVP

0.83

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