7-143324442-C-T

Position:

chr7-143324442-C-T

Variant summary

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

The NM_000083.3(CLCN1):c.803C>T(p.Thr268Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,764 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T268T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.14

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 7-143324442-C-T is Pathogenic according to our data. Variant chr7-143324442-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143324442-C-T is described in Lovd as [Pathogenic]. Variant chr7-143324442-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-143324442-C-T 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.803C>T	p.Thr268Met	missense_variant	7/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.908C>T		non_coding_transcript_exon_variant	7/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.803C>T	p.Thr268Met	missense_variant	7/23	1	NM_000083.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152106

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251490

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727128

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74282

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000354

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2023	Has been reported previously as a heterozygous variant along with another second variant (phase unknown) in patients with myotonia congenita in published literature (Deymeer et al., 1998; Michel et al., 2007; Sklov et al., 2013; Suetterlin et al., 2021); Has been reported as a single heterozygous variant in patients with myotonia congenita (Brugnoni et al., 1999; Michel et al., 2007; Suetterlin et al., 2021); Has also been reported in other cases with myotonia congenita, however specifics about segregation or presence of a second variant were not specified in these reports (Ferrandini et al., 2017; Ivanova et al., 2012; Stuennenberg et al., 2018); Published functional studies demonstrate a damaging effect on the gating process (Duffield et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25088311, 29606556, 24705798, 17654559, 32407401, 21221019, 32010054, 9736066, 36628841, 34789418, 31069529, 34529042, 24349310, 23113340, 10533075, 12566541, 28427807) -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 268 of the CLCN1 protein (p.Thr268Met). This variant is present in population databases (rs80356687, gnomAD 0.005%). This missense change has been observed in individuals with autosomal dominant myotonia congenita and autosomal recessive myotonia congenita (PMID: 9736066, 10533075, 17654559, 21221019, 23113340, 24349310). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21047). 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: 12566541). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

A Homozygote Missense variant c.803C>T in Exon 7 of the CLCN1 gene that results in the amino acid substitution p.Thr268Met was identified. The observed variant has a minor allele frequency of 0.00001/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic and LikelyPathogenic (Variant ID: 21047). This variant has previously been reported for myotonia congnita (Brugnoni R et al., 1999). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.99

MVP

0.98

MPC

0.73

ClinPred

0.94

GERP RS

4.8

Varity_R

0.69

gMVP

0.87

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