rs768119034

Positions:

• chr7-143339286-ATACCCTGCGGAGGC-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.1437_1450delACCCTGCGGAGGCT​(p.Pro480fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CLCN1 NM_000083.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1 O:1
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-143339286-ATACCCTGCGGAGGC-A is Pathogenic according to our data. Variant chr7-143339286-ATACCCTGCGGAGGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143339286-ATACCCTGCGGAGGC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1437_1450delACCCTGCGGAGGCT	p.Pro480fs	frameshift_variant	13/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1392_1405delACCCTGCGGAGGCT		non_coding_transcript_exon_variant	12/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1437_1450delACCCTGCGGAGGCT	p.Pro480fs	frameshift_variant	13/23	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*722_*735delACCCTGCGGAGGCT		non_coding_transcript_exon_variant	13/23	1		ENSP00000395949.2
CLCN1	ENST00000432192.6	n.*722_*735delACCCTGCGGAGGCT		3_prime_UTR_variant	13/23	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1437_1450delACCCTGCGGAGGCT	p.Pro480fs	frameshift_variant	13/23			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251488 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461338 Hom.: 0 AF XY: 0.000132 AC XY: 96 AN XY: 727034

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: 0.000152

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74356

Gnomad4 AFR AF: 0.0000724

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: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	Observed with a pathogenic variant in a patient with myotonia congenita, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Brugnoni et al., 2013); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23113340, 25438602, 7581380, 9040760, 33263785, 31589614, 23739125, 7951215) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CLCN1: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2024	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 17932099, 18337730, 23739125, 24349310, 34529042, 33263785), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 23893571). -

Congenital myotonia, autosomal recessive form Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The c.1437_1450del (p.(Pro480Hisfs*24)) variant was found in a heterozygous state in 3 Slovak patients with Myotonia congenita and in all of them also the second Likely Pathogenic variant was found: in two of them it was c.2680C>T (p.(Arg894*), whereas in the last one c.2364+2T>C splicing variant. The c.1437_1450del variant is listed as a disease-causing in the HGMD database (CD941645). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000121. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	research	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	May 22, 2024	PM2_supporting: this variant is absent from gnomAD v4.0 (adequate coverage >20X confirmed). The highest population allele frequency in gnomAD v3.1.2 is 0.00016 (0.016%; 11/68038 alleles in European non-Finnish population). PM3_verystrong: this variant has been found in a compound heterozygous state in multiple individuals with AR myotonia congenital (>4 points). PVS1 met: frameshift variant predicted to undergo NMD. Exon is present in a biologically relevant transcript in a gene where LOF is a known mechanism of disease. PS4 met: this variant has been described in more than 10 unrelated probands with consistent phenotype for disorder. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Pro480Hisfs*24) in the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). This variant is present in population databases (rs768119034, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive myotonia congenita (PMID: 7951215, 18337730, 22649220, 23739125, 24349310). This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 7951215, 23893571); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 279778). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PM3_VeryStrong+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 13, 2024	- -

Congenital myotonia, autosomal dominant form Pathogenic:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 10-22-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -

Batten-Turner congenital myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

The CLCN1 c.1437_1450delACCCTGCGGAGGCT (p.Pro480HisfsTer24) variant results in a frameshift variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Pro480HisfsTer24 variant has been reported in at least 14 individuals with myotonia congenita (MC), which includes three in a homozygous state and six in a compound heterozygous state (Meyer-Kleine et al. 1994; Lehmann-Horn et al. 1995; Meyer-Kleine et al. 1995; Mailander et al. 1996; Fialho et al. 2007; Dupre et al. 2009; Raja Rayan et al. 2012; Brugnoni et al. 2013). The variant appears to be associated with an autosomal recessive inheritance pattern, as the majority of evaluated heterozygous family members were unaffected. However, a single clinically unaffected heterozygous male was reported to display latent myotonia (Mailander et al. 1996). Homozygosity for the variant also reportedly results in a more severe phenotype associated with transient weakness and severely reduced chloride conductance in muscle fibers, consistent with features of recessive MC. The p.Pro480HisfsTer24 variant was absent from at least 660 control chromosomes and is reported at a frequency of 0.000150 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro480HisfsTer24 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. -

Smith-Lemli-Opitz syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 28, 2021

- -

Tip-toe gait Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Nov 15, 2022

Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Autosomal dominant intermediate Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Cologne University

Apr 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs768119034; hg19: chr7-143036379;