rs756199349
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000083.3(CLCN1):c.1231G>T(p.Gly411Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G411G) has been classified as Likely benign.
Frequency
Consequence
NM_000083.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1231G>T | p.Gly411Cys | missense_variant | 11/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1336G>T | non_coding_transcript_exon_variant | 11/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1231G>T | p.Gly411Cys | missense_variant | 11/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*516G>T | 3_prime_UTR_variant, NMD_transcript_variant | 11/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1231G>T | p.Gly411Cys | missense_variant | 11/23 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461724Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727180
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Congenital myotonia, autosomal recessive 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.1231G>T (p.(Gly411Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also heterozygous Likely pathogenic variant c.2680C>T. The c.1231G>T variant is listed as a disease-causing in the HGMD database (CM187251) and it has been published for the first time in PMID: 29606556. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.00000318. When transfected into HEK293 cells, the variant did not properly traffick to the cell surface. When these transfected cells were treated with MG132, the trafficking defect was rescued but cells expressing the variant still failed to produce a chloride current when examined via patch-clamp analysis, indicating the variant produces a non-functional chloride channel (PMID: 33013670) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: CLCN1 c.1231G>T (p.Gly411Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). c.1231G>T has been reported in the literature in compound heterozygous individuals affected with Autosomal Recessive Myotonia Congenita (e.g. Stunnenberg_2018, Altamura_2020). These data indicate that the variant may be associated with disease. When transfected into HEK293 cells, the variant did not properly traffick to the cell surface. When these transfected cells were treated with MG132, the trafficking defect was rescued but cells expressing the variant still failed to produce a chloride current when examined via patch-clamp analysis, indicating the variant produces a non-functional chloride channel (Altamura_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33013670, 29606556). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | clinical testing | GeneDx | Dec 22, 2017 | The G411C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G411C variant is not observed in large population cohorts (Lek et al., 2016). The G411C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with myotonia (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 08, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 33013670). 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: 429659). This missense change has been observed in individual(s) with autosomal recessive myotonic congenita (PMID: 29606556, 33013670; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 411 of the CLCN1 protein (p.Gly411Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at