rs797045032

chr7-143321720-GG-TC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP3 PP5

The NM_000083.3(CLCN1):c.568_569delinsTC(p.Gly190Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G190R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 10.0

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 10 ACMG points.

• PS1: Transcript NM_000083.3 (CLCN1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000083.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143321721-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1486657.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 id is 209139.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=8, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.568_569delinsTC	p.Gly190Ser	missense_variant	5/23	ENST00000343257.7
CLCN1	NR_046453.2	n.670_671delinsTC		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.568_569delinsTC	p.Gly190Ser	missense_variant	5/23	1	NM_000083.3	P4

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 11, 2022	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2021	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) -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:2

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.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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2023	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. -

Congenital myotonia, autosomal recessive form Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 26, 2013	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2024	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. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Congenital Myotonia, Autosomal Recessive Form (4.4e-05 vs ND), allowing no conclusion about variant significance. c.568_569delinsTC has been reported in the literature in multiple individuals affected with Congenital Myotonia, Autosomal Recessive Form. 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. The most pronounced variant effect results in <10% of normal activity. ClinVar contains an entry for this variant (Variation ID: 209139). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Congenital myotonia, autosomal dominant form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Sep 27, 2021

- -

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: rs797045032; hg19: chr7-143018813;