rs80356690
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000083.3(CLCN1):c.870C>G(p.Ile290Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
CLCN1
NM_000083.3 missense
NM_000083.3 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 0.161
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a helix (size 9) in uniprot entity CLCN1_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000083.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957
PP5
Variant 7-143330788-C-G is Pathogenic according to our data. Variant chr7-143330788-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143330788-C-G is described in Lovd as [Pathogenic]. Variant chr7-143330788-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital myotonia, autosomal recessive form Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2024 | Variant summary: CLCN1 c.870C>G (p.Ile290Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes. c.870C>G has been reported in the literature in nine heterozygous individuals in two families affected with Myotonia congenita and this variant show segregation with disease (Lehmann-Horn_1995, Koty_1996). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8857727, 7581380). ClinVar contains an entry for this variant (Variation ID: 17539). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 03, 2020 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study shows this variant causes a reduction of the gate open probability (PMID: 10051520). Computational tools predict that this variant is damaging. - |
CLCN1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 11, 2023 | The CLCN1 c.870C>G variant is predicted to result in the amino acid substitution p.Ile290Met. This variant has been reported in several individuals with autosomal dominant congenital myotonia (see for example, Lehmann-Horn et al. 1995. PubMed ID: 7581380; Brugnoni et al. 2013. PubMed ID: 23739125; Vereb et al. 2020. PubMed ID: 33263785; Babić Božović et al. 2021. PubMed ID: 34106991). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 05, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10051520, 10962018). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function. ClinVar contains an entry for this variant (Variation ID: 17539). This missense change has been observed in individuals with autosomal dominant congenital myotonia (PMID: 758138, 12390967, 23739125, 25036107). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive congenital myotonia (PMID: 23739125); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 290 of the CLCN1 protein (p.Ile290Met). - |
Congenital myotonia, autosomal dominant form Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1995 | - - |
Myotonia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Batten-Turner congenital myopathy Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
.;D
REVEL
Pathogenic
Sift
Pathogenic
.;D
Sift4G
Pathogenic
.;D
Polyphen
1.0
.;D
Vest4
0.95
MutPred
Gain of phosphorylation at T295 (P = 0.1265);Gain of phosphorylation at T295 (P = 0.1265);
MVP
0.95
MPC
0.74
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at