7-143351678-C-T

Variant names:

• chr7-143351678-C-T
• rs55960271
• NM_000083.3:c.2680C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1_Strong PS3 PP5_Very_Strong BS2_Supporting

The NM_000083.3(CLCN1):​c.2680C>T​(p.Arg894*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,614,164 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002555960: Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced chloride currents compared to wild type (Meyer-Kleine_1995)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R894R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: CLCN1 NM_000083.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:36 O:2
• Conservation: PhyloP100: 1.07
• Publications: 69 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002555960: Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced chloride currents compared to wild type (Meyer-Kleine_1995).; SCV004100819: PS3 supporting: functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.; SCV005399115: "In vitro studies using L6 myotubes and rat myofibers showed protein with the variant was exported normally from ER but was unstable (PMID: 17990293). An earlier study showed the variant resulted in a large reduction, but not complete abolition of chloride conductance in Xenopus oocytes (PMID: 8533761)."; SCV000966882: "In vitro functional studies provide some evidence that the p.Arg894X variant impacts protein function (Meyer-Kleine 1995)."; SCV000467134: Functional studies in Xenopus oocytes demonstrated that the variant resulted in greatly reduced choride currents compared to wild type, to a level that was intermediate between the reductions seen for a known “fully dominant” pathogenic variant, and a known “fully recessive” pathogenic variant (Meyer-Kleine et al. 1995).; SCV000329301: Published functional studies demonstrate a damaging effect; R894X destabilizes the protein, possibly leading to reduced expression, and greatly reduces chloride currents in vitro (PMID: 8533761, 17990293);; SCV000612784: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8533761, 17107341).; SCV000636295: Experimental studies have shown that this premature translational stop signal affects CLCN1 function (PMID: 8533761, 17990293).; SCV001786716: Through in-vitro analyzes it could be shown that the detected variant has a dominant-negative effect on the function of the chloride channel [Meyer-Kleine (1995) Am J Hum Genet 57: 1325]; SCV005345204: Functional studies have found that this variant may cause a dramatic reduction, but not a full loss, of chloride currents (Meyer-Kleine et al. 1995. PubMed ID: 8533761).
• PP5: Variant 7-143351678-C-T is Pathogenic according to our data. Variant chr7-143351678-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2680C>T	p.Arg894*	stop_gained	Exon 23 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.2635C>T		non_coding_transcript_exon	Exon 22 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.2680C>T	p.Arg894*	stop_gained	Exon 23 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*1965C>T		non_coding_transcript_exon	Exon 23 of 23	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000432192.6	TSL:1	n.*1965C>T		3_prime_UTR	Exon 23 of 23	ENSP00000395949.2	H7C0N6

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00288 AC: 716 AN: 248982 AF XY: 0.00278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00222 AC: 3242 AN: 1461892 Hom.: 12 Cov.: 32 AF XY: 0.00219 AC XY: 1594 AN XY: 727248

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.0172 AC: 918 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00195 AC: 2171 AN: 1112010

Other (OTH) AF: 0.00169 AC: 102 AN: 60396

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00289 AC XY: 215 AN XY: 74450

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00334 AC: 227 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00248 Hom.: 6

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	not provided (11)
9	-	-	Congenital myotonia, autosomal recessive form (9)
5	-	-	Congenital myotonia, autosomal dominant form (5)
5	-	-	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (5)
1	-	-	Abnormality of the musculature (1)
1	-	-	Batten-Turner congenital myopathy (2)
1	-	-	Cerebral palsy (1)
1	-	-	CLCN1-related disorder (1)
1	-	-	Myopathy;C4021726:EMG: myopathic abnormalities (1)
1	-	-	Tip-toe gait (1)
-	-	-	Myotonia levior;C0751360:Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.49	N
PhyloP100		1.1
Vest4		0.68
GERP RS		2.9
Mutation Taster		=53/147	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs55960271; hg19: chr7-143048771; COSMIC: COSV58367397; COSMIC: COSV58367397;