rs80356701

Positions:

chr7-143330838-T-C

Variant summary

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

The NM_000083.3(CLCN1):c.920T>C(p.Phe307Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.01

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000083.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 7-143330838-T-C is Pathogenic according to our data. Variant chr7-143330838-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 21050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330838-T-C 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.920T>C	p.Phe307Ser	missense_variant	8/23	ENST00000343257.7
CLCN1	NR_046453.2 linkuse as main transcript	n.1025T>C		non_coding_transcript_exon_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.920T>C	p.Phe307Ser	missense_variant	8/23	1	NM_000083.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251440

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135896

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:

0.000139

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

727244

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:

0.000168

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

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:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000794

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2022	Reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jorgensen et al., 2003; Fialho et al., 2007; Wang et al., 2022); Published functional studies demonstrate a shift in voltage dependence towards positive potentials, and the altered protein displayed a dominant-negative effect when expressed with wild type protein (Kubisch et al., 1998; Aromataris et al., 2001); Not observed at a 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: 24349310, 11840191, 11408615, 17932099, 15162127, 12661046, 23152584, 23516313, 32010054, 32906206, 34529042, 35350395, 9736777) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with myotonia congenita together with a single recessive pathogenic variant in the same gene (PMID: 17932099, 12661046, 35350395), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 23516313, 23152584). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11408615, 9736777. -

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

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CLCN1 protein (p.Phe307Ser). This variant is present in population databases (rs80356701, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 9736777, 17932099, 23152584, 23516313). 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: 21050). 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, 11408615). For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2024	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 20, 2022	ACMG codes: PS4_Moderate, PS3, PM2, PP3 -

Batten-Turner congenital myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 18, 2018

The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. 1998; Sun et al. 2001; Colding-Jorgensen et al. 2003; Fialho et al. 2007; Raheem et al. 2012; Horga et al. 2013). In the majority of cases, the variant acted in an autosomal dominant manner, but several of cases of compound heterozygosity and autosomal recessive inheritance were also reported. The p.Phe307Ser variant was absent from 50 controls but is reported at a frequency of 0.000155 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in Xenopus oocytes showed a shifted voltage dependence of the variant channel that was expected to prevent efficient repolarization of the muscle action potential, a finding that has been seen with other disease-causing variants. (Kubisch et al. 1998; Aromataris et al. 2001). Based on the collective evidence, the p.Phe307Ser variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

CLCN1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

The CLCN1 c.920T>C variant is predicted to result in the amino acid substitution p.Phe307Ser. This variant has been reported in multiple unrelated individuals and families with myotonia congenita (Kubisch et al. 1998. PubMed ID: 9736777; Sun et al. 2001. PubMed ID: 11840191; Fialho et al. 2007. PubMed ID: 17932099; Raheem et al. 2012. PubMed ID: 23152584; Horga et al. 2013. PubMed ID: 23516313). In most cases, this variant has displayed dominant inheritance but it has also been reported in the homozygous or compound heterozygous state with another pathogenic variant (Fialho et al. 2007. PubMed ID: 17932099; Horga et al. 2013. PubMed ID: 23516313). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143027931-T-C). This variant is interpreted as pathogenic. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

Polyphen

1.0

.;D

Vest4

0.98

MVP

0.99

MPC

1.0

ClinPred

0.99

GERP RS

4.6

Varity_R

0.97

gMVP

0.90

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