rs150885084
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong
The NM_000083.3(CLCN1):c.854G>A(p.Gly285Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G285R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000083.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLCN1 | NM_000083.3 | c.854G>A | p.Gly285Glu | missense_variant, splice_region_variant | 8/23 | ENST00000343257.7 | |
CLCN1 | NR_046453.2 | n.959G>A | splice_region_variant, non_coding_transcript_exon_variant | 8/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLCN1 | ENST00000343257.7 | c.854G>A | p.Gly285Glu | missense_variant, splice_region_variant | 8/23 | 1 | NM_000083.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251352Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135850
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.0000921 AC XY: 67AN XY: 727190
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74484
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2022 | Observed in an affected mother and son with myotonia with presumed autosomal dominant inheritance (Thomas et al., 2008); Published functional studies demonstrate that the G285E variant leads to absent expression of chloride currents (Kubisch et al., 1998); 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; This variant is associated with the following publications: (PMID: 24037712, 15162127, 29606556, 18816629, 9736777, 11933197, 15786415, 18337730, 12390967, 29050397, 12210360, 22995991, 28662944, 12661046, 23810313, 31589614, 17932099, 34529042) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 13, 2023 | PP1, PP3, PM2, PM3, PS3, PS4_moderate - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 29, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 06, 2020 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is primarily reported as autosomal recessive myotonia congenita (PMID: 9736777 15786415, 17932099, 18337730, 21387378, 24037712, 28662944), however, it has also been reported as autosomal dominant myotonia congenita (PMID: 18816629). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant causes loss of channel function as demonstrated by abrogation of chloride current (PMID 9736777). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 285 of the CLCN1 protein (p.Gly285Glu). This variant is present in population databases (rs150885084, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 9736777, 12390967, 18337730, 21387378, 24037712). ClinVar contains an entry for this variant (Variation ID: 280100). 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: 9736777). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 16, 2021 | The c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene substitutes a well conserved Glycine for Glutamic Acid at amino acid 285/989 (exon 8/23). This variant is found with low frequency in gnomAD(v3.1.1) (5 heterozygotes, 0 homozygotes; allele frequency: 3.29e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.93) to the function of the canonical transcript. This variant is reported as Pathogenic in ClinVar (VarID:280100) and has been identified in many affected individuals in the literature in homozygosity or compound heterozygosity with another variant [PMID:18337730; PMID: 24037712; others], and in some individuals with presumed autosomal recessive inheritance but without a second variant identified [PMID: 9736777; PMID:21387378; PMID: 24037712; others], as well as in one family with an affected mother and son and presumed autosomal dominant inheritance pattern [PMID:18816629]. Functional studies demonstrate the p.Gly285Glu variant leads to absence of chloride currents [PMID:9736777]. Given its identification in many affected individuals in the literature, functional studies showing deleterious effect, low frequency in population databases, and in silico algorithms prediction of a deleterious effect, the c.854G>A (p.Gly285Glu) variant identified in the CLCN1 gene is reported as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 14, 2022 | - - |
Smith-Lemli-Opitz syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 28, 2021 | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Oct 10, 2022 | Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. - |
CLCN1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 11, 2024 | The CLCN1 c.854G>A variant is predicted to result in the amino acid substitution p.Gly285Glu. This variant has been reported in patients with autosomal recessive myotonia congenita (see, for example, Kubisch et al. 1998. PubMed ID: 9736777; Trip et al. 2008. PubMed ID: 18337730). In addition, it has been documented in the heterozygous state among several individuals with presumed autosomal recessive disease (Kubisch et al. 1998. PubMed ID: 9736777, Tan et al. 2014. PubMed ID: 24037712) and in at least one affected mother and her son with presumed autosomal dominant inheritance (Thomas et al. 2008. PubMed ID: 18816629). Functional studies on this variant have demonstrated that it affects chloride channel function (Kubisch et al. 1998. PubMed ID: 9736777). Of note, c.854G is the first base of exon eight and therefore this change may be more likely to impact splicing; however, visual inspection of splicing in silico predictions does not indicate a large impact (Alamut Visual Plus v1.6.1). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/280100/). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic for autosomal recessive CLCN1-related disorders; however, it is uncertain in the context of an autosomal dominant mode of inheritance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at