rs80356691

Positions:

chr7-143330847-C-T

Variant summary

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

The NM_000083.3(CLCN1):c.929C>T(p.Thr310Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,076 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., 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:4O:1

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:

CLCN1 (HGNC:):

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 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, 0.94

PP5

Variant 7-143330847-C-T is Pathogenic according to our data. Variant chr7-143330847-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330847-C-T 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.929C>T	p.Thr310Met	missense_variant	8/23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 linkuse as main transcript	n.1034C>T		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.929C>T	p.Thr310Met	missense_variant	8/23	1	NM_000083.3	ENSP00000339867.2		P35523

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 03, 2016

- -

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 14, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 310 of the CLCN1 protein (p.Thr310Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myotonia congenita (PMID: 12390967, 15311340, 19949657; Invitae). This variant has been reported in individual(s) with autosomal recessive myotonia congenita (PMID: 18263754); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 21051). 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 80%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 12390967, 12566541). For these reasons, this variant has been classified as Pathogenic. -

Congenital myotonia, autosomal dominant form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2024

Variant summary: CLCN1 c.929C>T (p.Thr310Met) 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 1.9e-06 in 1614076 control chromosomes. c.929C>T has been reported in the literature in the heterozygous state in multiple individuals affected with autosomal dominant myotonia (e.g. Wu_2002, Jacobsen_2024, Meyer_2020, Jou_2004, Bernard_2021, Vereb_2021, Moon_2009) and in the homozygous state in at least one individual with more severe symptoms of myotonia (e.g. Bernard_2021). These data indicate that the variant is very likely to be associated with disease. Experimental studies show that this variant impacts CIC-1 gating in vitro (e.g. Wu_2002, Duffield_2003). The following publications have been ascertained in the context of this evaluation (PMID: 18263754, 12566541, 38270354, 15311340, 32670189, 19949657, 33263785, 12390967). ClinVar contains an entry for this variant (Variation ID: 21051). Based on the evidence outlined above, the variant was classified as pathogenic in association with autosomal dominant myotonia. -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.T310M in CLCN1 (NM_000083.3) has been reported both in autosomal dominant as well as recessive myotonia congenita (Bernard G et al; Wu Fen-Fen et al).Functional studies suggest a damaging effect by affecting the opening rate (Duffield M et al). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes and 1000 Genome. The p.T310M missense variant is predicted to be damaging by both SIFT and PolyPhen2 and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -

Batten-Turner congenital myopathy

Other:1

not provided, no classification provided

literature only

GeneReviews

Associated with autosomal recessive and autosomal dominant mode of inheritance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.0

.;L

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.5

.;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0070

.;D

Polyphen

1.0

.;D

Vest4

0.84

MutPred

0.82

Loss of catalytic residue at T310 (P = 0.0895);Loss of catalytic residue at T310 (P = 0.0895);

MVP

0.98

MPC

0.72

ClinPred

0.98

GERP RS

4.6

Varity_R

0.65

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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