Genetic Variant NM_000083.3:c.689G>A (chr7-143321841-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3PM1PP2PP3_StrongPP5_Very_Strong

The NM_000083.3(CLCN1):c.689G>A(p.Gly230Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002038563: Heterologous expression of the p.Gly230Glu variant in Xenopus oocytes suggest the variant exerts a dominant negative effect on the channel. Additional work in mammalian cell lines showed that the p.Gly230Glu variant induced changes in ion selectivity relative to the wildtype protein (Steinmeyer et al. 1994; Fahlke et al. 1997).; SCV000329298: Published functional studies have demonstrated that the Gly230 residue resides within the chloride channel pore and the p.(G230E) variant dramatically alters pore properties (PMID:9122265); SCV000612794: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:9122265, 8112288); SCV000649787: Experimental studies have shown that this missense change affects CLCN1 function (PMID:8112288, 9122265).; SCV004020403: The most pronounced variant effect results in altered pore properties of the muscle chloride channel (Fahle_1997) and destroy normal channel activity while exerting a dominant negative effect of wild-type channels (Steinmeyer_1994). PMID:9122265, 23516313, 8112288, 34529042; SCV004726910: Functional studies suggested that the p.Gly230Glu substitution dramatically altered the pore properties of CLCN1 (Fahlke et al. 1997. PMID:9122265).".

Frequency

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

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:2

Conservation

PhyloP100: 8.19

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

myotonia congenita, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
myotonia congenita, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Thomsen and Becker disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002038563: Heterologous expression of the p.Gly230Glu variant in Xenopus oocytes suggest the variant exerts a dominant negative effect on the channel. Additional work in mammalian cell lines showed that the p.Gly230Glu variant induced changes in ion selectivity relative to the wildtype protein (Steinmeyer et al. 1994; Fahlke et al. 1997).; SCV000329298: Published functional studies have demonstrated that the Gly230 residue resides within the chloride channel pore and the p.(G230E) variant dramatically alters pore properties (PMID: 9122265); SCV000612794: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9122265, 8112288); SCV000649787: Experimental studies have shown that this missense change affects CLCN1 function (PMID: 8112288, 9122265).; SCV004020403: The most pronounced variant effect results in altered pore properties of the muscle chloride channel (Fahle_1997) and destroy normal channel activity while exerting a dominant negative effect of wild-type channels (Steinmeyer_1994). PMID: 9122265, 23516313, 8112288, 34529042; SCV004726910: Functional studies suggested that the p.Gly230Glu substitution dramatically altered the pore properties of CLCN1 (Fahlke et al. 1997. PMID: 9122265).

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000083.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 106 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 0.21191 (below the threshold of 3.09). Trascript score misZ: 0.95247 (below the threshold of 3.09). GenCC associations: The gene is linked to myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Thomsen and Becker disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 7-143321841-G-A is Pathogenic according to our data. Variant chr7-143321841-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.689G>A	p.Gly230Glu	missense	Exon 5 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.791G>A		non_coding_transcript_exon	Exon 5 of 22

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.689G>A	p.Gly230Glu	missense	Exon 5 of 23	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6	TSL:1	n.455G>A		non_coding_transcript_exon	Exon 4 of 23	ENSP00000395949.2	H7C0N6
CLCN1	ENST00000455478.6	TSL:1	n.143G>A		non_coding_transcript_exon	Exon 2 of 7	ENSP00000400027.2	H7C1F4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152254

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

251000

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Congenital myotonia, autosomal dominant form (2)

Congenital myotonia, autosomal recessive form (2)

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (3)

CLCN1-related disorder (1)

Batten-Turner congenital myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.4

PhyloP100

8.2

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MVP

0.99

MPC

0.85

ClinPred

1.0

GERP RS

5.0

Varity_R

0.98

gMVP

0.98

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over