rs756981034
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_000083.3(CLCN1):c.1261C>T(p.Arg421Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,928 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R421H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000083.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.1261C>T | p.Arg421Cys | missense_variant | 12/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1356+230C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.1261C>T | p.Arg421Cys | missense_variant | 12/23 | 1 | NM_000083.3 | P4 | |
CLCN1 | ENST00000432192.6 | c.*546C>T | 3_prime_UTR_variant, NMD_transcript_variant | 12/23 | 1 | ||||
CLCN1 | ENST00000650516.2 | c.1261C>T | p.Arg421Cys | missense_variant | 12/23 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251462Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135902
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461774Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727210
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 23, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2022 | Reported in association with CLCN1-related myotonia congenita (Ivanova et al., 2012; Morrow et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel current (Mazon et al., 2012; Suetterlin et al., 2021); This variant is associated with the following publications: (PMID: 31589614, 34529042, 23113340, 22094069, 23739125, 24349310, 23810313) - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | This variant is present in population databases (rs756981034, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22094069). 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: 447047). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22094069, 23113340, 23739125). This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 23113340); however, the role of the variant in this condition is currently unclear. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 421 of the CLCN1 protein (p.Arg421Cys). - |
Congenital myotonia, autosomal recessive form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2023 | Variant summary: CLCN1 c.1261C>T (p.Arg421Cys) 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 2.4e-05 in 251462 control chromosomes (gnomAD). c.1261C>T has been reported in the literature in multiple compound heterozygous individuals affected with Myotonia congenital (Mazon_2012, Brugnoni_2013, Suetterlin_2022). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study reports this variant results in a reduction of the wild-type activity (Mazon_2012). The following publications have been ascertained in the context of this evaluation (PMID: 23739125, 22094069, 34529042). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at