rs797045032

Variant names:

• chr7-143321720-GG-TC
• rs797045032
• NM_000083.3:c.568_569delGGinsTC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3 PP5

The NM_000083.3(CLCN1):​c.568_569delGGinsTC​(p.Gly190Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000437 in 11 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G190R) has been classified as Likely pathogenic.

• Frequency: GnomAD MNV: 𝑓 0.000044 Genomes: not found (cov: 33)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:1
• Conservation: PhyloP100: 10.0
• Publications: 22 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143321720-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289004.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-143321720-GG-TC is Pathogenic according to our data. Variant chr7-143321720-GG-TC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209139.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.568_569delGGinsTC	p.Gly190Ser	missense_variant		ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.670_671delGGinsTC		non_coding_transcript_exon_variant	Exon 5 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.568_569delGGinsTC	p.Gly190Ser	missense_variant		1	NM_000083.3	ENSP00000339867.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

GnomAD MNV AF: 0.0000437 AC: 11 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Jan 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22921319, 23113340), however, it has also been reported in individuals with autosomal dominant myotonia congenita (PMID: 23113340, 19697366, 22921319). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair channel function by reducing permeability, current density and affecting channel deactivation properties (PMID: 22521272, 23933576). -

Dec 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published electrophysiological studies in HEK293 cells showed a dramatic positive shift in voltage-dependent activation and highly reduced chloride currents (Desaphy et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 23739125, 32117024, 32664137, 23933576, 22921319, 23113340, 24349310, 19697366, 22521272, 29606556, 32558419, 33013670, 32655465, 29809153) -

Aug 17, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLCN1: PM3:Very Strong, PM2, PS3:Supporting -

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

-

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.568_569delinsTC (p.(Gly190Ser)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita. No other Pathogenic or Likely pathogenic variants were found in this individual. According to PMID: 26007199, this variant is found in the highly conserved ClC-1 helix D motif, which plays a critical role in the chloride ion pathway. This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22921319, 23113340), however, it has also been reported in individuals with autosomal dominant myotonia congenita (PMID: 23113340, 19697366, 22921319). As shown in PMID: 23933576, this variant in the heterozygous state manifests as asymptomatic or with only mild manifestations. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the CLCN1 protein (p.Gly190Ser). This variant is present in population databases (rs797045032, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22521272, 22921319, 23739125, 24349310, 26007199). It has also been observed to segregate with disease in related individuals; in the heterozygous state this variant was reported to be incompletely penetrant and in the homozygous state it was reported to cause a more severe phenotype (PMID: 19697366, 22921319). ClinVar contains an entry for this variant (Variation ID: 209139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22521272, 23933576). For these reasons, this variant has been classified as Pathogenic. -

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myotonia, autosomal recessive form Pathogenic:3

Mar 26, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLCN1 c.568_569delinsTC (p.Gly190Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251480 control chromosomes (gnomAD). c.568_569delinsTC has been reported in the literature in multiple individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g. Shalata_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a dramatic shift in voltage dependence of channel activation (Desaphy_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19697366, 23933576). ClinVar contains an entry for this variant (Variation ID: 209139). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This multinucleotide sequence change in CLCN1 is predicted to replace glycine with serine at codon 190, p.(Gly190Ser). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the transmembrane D helix (PMID: 37892996). There is a small physicochemical difference between glycine and serine. The highest expected population minor allele frequency in the population database gnomAD v4.1 is 0.005% (56/1,180,050 alleles) in the European (non-Finnish) population, consistent with recessive disease. ClinVar contains an entry for this variant (Variation ID: 209139). This variant has been detected as homozygous and compound heterozygous in multiple individuals with myotonia congenita, with at least one pathogenic variant confirmed on the second allele (PMID: 19697366, 22521272, 34529042, 24349310, 29606556), and appeared to segregate with disease in one family (PMID: 19697366). Affected heterozygotes have been reported with a milder phenotype, and the variant appears to segregate with disease in these families (PMID: 23113340, 22921319, 19697366). Functional studies are supportive of a damaging effect on protein function (PMID: 23933576, 22521272, 34529042). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PM3_Very Strong, PS3_Supp, PP1. -

Nov 26, 2013

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory with a known pathogenic missense variant (F167L; phase unknown) in a 46-year-old male with heart arrhythmia, hypertrophic cardiomyopathy, neuromuscular disease, EMG evidence of myopathy with myotonic discharges and mild length-dependent neuropathy, poor balance, short stature, scoliosis, small hands. -

Headache;C0026837:Rigidity;C0027051:Myocardial infarction;C0042571:Vertigo;C4022169:EMG: myotonic discharges;C4022683:Myotonia of the upper limb Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLCN1-related disorder Pathogenic:1

Aug 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CLCN1 c.568_569delinsTC variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in the homozygous state or with a second CLCN1 variant in many individuals with myotonia congenita (see, for example, Shalata et al. 2010. PubMed ID: 19697366; Ulzi et al. 2012. PubMed ID: 22521272; Supplementary Table 1, Suetterlin et al. 2022. PubMed ID: 34529042). Some heterozygous individuals have been reported to have mild features as well (Shalata et al. 2010. PubMed ID: 19697366; Portaro et al. 2012. PubMed ID: 22921319). This variant has been noted to segregate with disease in families (Shalata et al. 2010. PubMed ID: 19697366; Orsin et ali. 2020. PubMed ID: 32117024). In vitro experimental studies suggest this variant affects protein function (Desaphy et al. 2013. PubMed ID: 23933576; Ulzi et al. 2012. PubMed ID: 2252127). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Congenital myotonia, autosomal dominant form Pathogenic:1

Sep 27, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=6/94	disease causing

Splicing

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

Other links and lift over

dbSNP: rs797045032; hg19: chr7-143018813;