rs80356701
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_000083.3(CLCN1):āc.920T>Cā(p.Phe307Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ).
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.920T>C | p.Phe307Ser | missense_variant | 8/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.1025T>C | non_coding_transcript_exon_variant | 8/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.920T>C | p.Phe307Ser | missense_variant | 8/23 | 1 | NM_000083.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251440Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135896
GnomAD4 exome AF: 0.000107 AC: 156AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82AN XY: 727244
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 10, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2022 | Reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jorgensen et al., 2003; Fialho et al., 2007; Wang et al., 2022); Published functional studies demonstrate a shift in voltage dependence towards positive potentials, and the altered protein displayed a dominant-negative effect when expressed with wild type protein (Kubisch et al., 1998; Aromataris et al., 2001); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24349310, 11840191, 11408615, 17932099, 15162127, 12661046, 23152584, 23516313, 32010054, 32906206, 34529042, 35350395, 9736777) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 26, 2022 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with myotonia congenita together with a single recessive pathogenic variant in the same gene (PMID: 17932099, 12661046, 35350395), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 23516313, 23152584). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11408615, 9736777. - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 12, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CLCN1 protein (p.Phe307Ser). This variant is present in population databases (rs80356701, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 9736777, 17932099, 23152584, 23516313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21050). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 9736777, 11408615). For these reasons, this variant has been classified as Pathogenic. - |
Congenital myotonia, autosomal dominant form Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Apr 20, 2022 | ACMG codes: PS4_Moderate, PS3, PM2, PP3 - |
Batten-Turner congenital myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 18, 2018 | The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. 1998; Sun et al. 2001; Colding-Jorgensen et al. 2003; Fialho et al. 2007; Raheem et al. 2012; Horga et al. 2013). In the majority of cases, the variant acted in an autosomal dominant manner, but several of cases of compound heterozygosity and autosomal recessive inheritance were also reported. The p.Phe307Ser variant was absent from 50 controls but is reported at a frequency of 0.000155 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in Xenopus oocytes showed a shifted voltage dependence of the variant channel that was expected to prevent efficient repolarization of the muscle action potential, a finding that has been seen with other disease-causing variants. (Kubisch et al. 1998; Aromataris et al. 2001). Based on the collective evidence, the p.Phe307Ser variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
CLCN1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 07, 2023 | The CLCN1 c.920T>C variant is predicted to result in the amino acid substitution p.Phe307Ser. This variant has been reported in multiple unrelated individuals and families with myotonia congenita (Kubisch et al. 1998. PubMed ID: 9736777; Sun et al. 2001. PubMed ID: 11840191; Fialho et al. 2007. PubMed ID: 17932099; Raheem et al. 2012. PubMed ID: 23152584; Horga et al. 2013. PubMed ID: 23516313). In most cases, this variant has displayed dominant inheritance but it has also been reported in the homozygous or compound heterozygous state with another pathogenic variant (Fialho et al. 2007. PubMed ID: 17932099; Horga et al. 2013. PubMed ID: 23516313). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143027931-T-C). This variant is interpreted as pathogenic. - |
Congenital myotonia, autosomal recessive form Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at