Submissions for variant NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys)

gnomAD frequency: 0.00028  dbSNP: rs121912799

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000184008	SCV000236506	pathogenic	Congenital myotonia, autosomal dominant form	2014-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000346725	SCV000329299	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Published functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (PMID: 17990293); 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: 1379744, 29790872, 23739125, 10690989, 7981750, 8301644, 9040760, 7951242, 11840191, 31589614, 12390967, 33263785, 18807109, 17932099, 34790634, 32670189, 18337730, 34758253, 34529042, 8533761, 17990293, 21204798)
Eurofins Ntd Llc (ga)	RCV000346725	SCV000331890	pathogenic	not provided	2016-06-28	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000184008	SCV000584084	pathogenic	Congenital myotonia, autosomal dominant form	2016-10-13	criteria provided, single submitter	research
Athena Diagnostics	RCV000346725	SCV000612755	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families with autosomal recessive myotonia congenita (PMID: 8533761, 21204798), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 17932099). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduces protein transport from the endoplasmic reticulum (PMID: 17990293). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638232	SCV000759718	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the CLCN1 protein (p.Phe413Cys). This variant is present in population databases (rs121912799, gnomAD 0.2%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 1379744, 8533761, 11840191, 18337730, 23739125). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17531). 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: 10690989, 17990293). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000346725	SCV001248207	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000346725	SCV001715971	pathogenic	not provided	2020-02-28	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM3, PP1, PP3
Revvity Omics, Revvity	RCV000346725	SCV002017365	pathogenic	not provided	2023-05-18	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002291268	SCV002583812	pathogenic	CLCN1-related disorder	2022-08-07	criteria provided, single submitter	clinical testing	PS3 PP3 PP1 PS4_Moderate PM3
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000019083	SCV005038730	likely pathogenic	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	research	The c.1238T>G (p.(Phe413Cys)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried also another Likely pathogenic variant in heterozygous state (c.2680C>T). The c.1238T>G variant is listed as a disease-causing in the HGMD database (CM920197) and it has been published for the first time in PMID: 1379744. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.000265.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000019083	SCV005203841	pathogenic	Congenital myotonia, autosomal recessive form	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1238T>G (p.Phe413Cys) 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 allele was found at a frequency of 0.00037 in 251472 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Congenital Myotonia, Autosomal Recessive Form, allowing no conclusion about variant significance. The variant c.1238T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g. Meyer-Kleine_1995, Periviita_2024). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in retention of the protein product in the endoplasmic reticulum (Papponen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 8533761, 38055022, 17990293). ClinVar contains an entry for this variant (Variation ID: 17531). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019083	SCV000039371	pathogenic	Congenital myotonia, autosomal recessive form	1993-11-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000184008	SCV001760194	likely pathogenic	Congenital myotonia, autosomal dominant form		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001548747	SCV001763566	pathogenic	Tip-toe gait	2020-08-18	flagged submission	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV002291268	SCV005363923	pathogenic	CLCN1-related disorder	2024-03-13	no assertion criteria provided	clinical testing	The CLCN1 c.1238T>G variant is predicted to result in the amino acid substitution p.Phe413Cys. This variant has been reported in multiple unrelated individuals with myotonia congenita (Koch et al. 1992. PubMed ID: 1379744; Papponen et al. 2008. PubMed ID: 17990293; Suominen et al. 2008. PubMed ID: 18807109; Brugnoni et al. 2013. PubMed ID: 23739125). This variant is reported in 0.25% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.