Submissions for variant NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu)

gnomAD frequency: 0.00075  dbSNP: rs149729531

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191068	SCV000245460	pathogenic	Congenital myotonia, autosomal dominant form	2015-07-09	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing in a recessive state, so heterozygotes would be carriers.
Baylor Genetics	RCV000191070	SCV000245462	uncertain significance	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415172	SCV000492914	likely pathogenic	Myotonia	2015-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000479583	SCV000564883	likely benign	not specified	2017-12-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000556194	SCV000636336	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 167 of the CLCN1 protein (p.Phe167Leu). This variant is present in population databases (rs149729531, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (Becker disease), and often co-occurs (likely on the same chromosome) with p.Arg105Cys (PMID: 17654559, 18337730, 21221019, 22094069, 22521272, 22641783, 23113340, 23739125, 24037712, 24304580, 24349310, 24452722, 27199537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209138). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CLCN1 function (PMID: 10690989, 23933576, 24304580, 26510092). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics	RCV000711233	SCV000841565	pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Therefore, the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 18337730, 21221019, 24037712, 23739125). Although there are heterozygous carriers with disease, this variant has also been reported in asymptomatic individuals (PMID: 17932099, 21698652, 26510092, 7874130, 27614575). Therefore, the data only supports a recessive association with CLCN1-related conditions. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000711233	SCV000892807	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	CLCN1: PM3, PM2:Supporting
Mendelics	RCV000191070	SCV001137531	uncertain significance	Congenital myotonia, autosomal recessive form	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000191070	SCV001367247	likely pathogenic	Congenital myotonia, autosomal recessive form	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000191070	SCV001423853	uncertain significance	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	research	The CLCN1 p.Phe167Leu (p.F167L) variant has been reported in several patients with Becker disease (PMID:26510092; 24304580; 17654559; 23739125). However, this variant has also been seen in unaffected individuals (PMID: 27614575). One study reported that the p.F167L variant was associated with more normal function than other deleterious variants and noted that compound heterozygous individuals with p.F167L had a more mild phenotype (PMID: 23933576).
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001753591	SCV001994829	pathogenic	Tip-toe gait	2021-06-25	criteria provided, single submitter	clinical testing	The variant causes the exchange of phenylanaline by leucine at position 167 of the CLCN1 protein and is located in one of the transmembrane helical motifs that play a role in the ion selectivity of the chloride channel. 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000711233	SCV002583811	uncertain significance	not provided	2022-08-07	criteria provided, single submitter	clinical testing	BP4
Revvity Omics, Revvity	RCV000711233	SCV003830777	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000711233	SCV004224117	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000479583	SCV004803337	uncertain significance	not specified	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.501C>G (p.Phe167Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 1614204 control chromosomes in the gnomAD database, including 5 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (0.00086 vs 0.0035), allowing no conclusion about variant significance. c.501C>G has been reported in the literature at a compound heterozygous state in individuals affected with autosomal recessive Myotonia congenita (examples, Gorukmez_2023, Bozovic_2021, Suetterlin_2022, Vereb_2020). It has also been reported at a heterozygous in several individuals with autosomal dominant Myotonia congenita and often along with a pathogenic variant from another gene that may fully explain the phenotype (example, Peddareddygari_2016, Maggi_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Myotonia congenita. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging or marginal effect of this variant on the electrophysiological metrics of CLCN1 by whole-cell patch clamping in HEK293T cells or in xenopus oocytes (Desaphy_2013, Zhang_2000, Suetterlin_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34106991, 23933576, 28993909, 27266866, 34529042, 10690989, 36964972). ClinVar contains an entry for this variant (Variation ID: 209138). Based on the evidence outlined above, the variant was classified as uncertain significance.
Molecular Genetics, Royal Melbourne Hospital	RCV000191070	SCV004812673	pathogenic	Congenital myotonia, autosomal recessive form	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change in CLCN1 is predicted to replace phenylalanine with leucine at codon 167, p.(Phe167Leu). The phenylalanine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the transmembrane alpha-helix C domain (PMID: 23739125, 34529042). There is a small physicochemical difference between phenylalanine and leucine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.1% (71/60,026 alleles, 1 homozygote) in the Admixed American population. This variant has been detected in the homozygous and compound heterozygous state (with at least one individual confirmed in trans with a pathogenic variant) in multiple individuals with autosomal recessive myotonia congenita (ARMC) (PMID: 22094069, 23739125, 28427807, 31544778, 33263785, 33573884, 34529042). The variant has been reported to segregate with ARMC in at least two families (PMID: 21221019). There are inconsistent reports of this variant heterozygous in association with autosomal dominant myotonia congenita (PMID: 21387378, 26510092, 27614575). This variant is also commonly reported in cis with c.313C>T p.(Arg105Cys) in individuals with ARMC (PMID: 21221019, 21387378, 22094069, 22109722, 23739125, 24349310, 28427807, 31544778, 33573884). Patch clamp assays measuring voltage-dependent activation in Xenopus oocytes and mammalian cell lines are conflicting from no obvious differences in chloride channel voltage to a modest positive shift in the voltage dependence of activation (PMID: 10690989, 23933576, 26510092, 34529042). The assay demonstrating a modest positive shift suggests the variant behaves similarly to ARMC variants without dominant-negative effects (PMID: 34529042). Computational evidence is uninformative for the missense substitution (REVEL = 576). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Moderate.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV000191070	SCV005038735	likely pathogenic	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	research	The c.501C>G p.(Phe167Leu)) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried another Likely Pathogenic variant c.959C>T (p.(Ala320Val)). c.501C>G variant is reported in the HGDM database as a disease-causing variant CM940283 and it was reported for the first time in PMID: 7874130. GnomAD ExomesVersion: 4.0 indicates the frequency of f = 0.000863.
GenomeConnect - Invitae Patient Insights Network	RCV000556194	SCV001749580	not provided	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000191070	SCV004697498	affects	Congenital myotonia, autosomal recessive form	2024-02-20	no assertion criteria provided	clinical testing	Advanced modeling of protein structural, functional, and spatial characteristics, amino acid conservations physicochemical variations, residues mobility, and thermodynamic stability details emerging from several studies indicate that the c.501C>G missense variant behaves similarly to the wild-type, with little or no evidence supportive of a deleterious effect for the CLCN1 channel. In consistence with the findings of the current cohort it could be suggested that c.501C>G, p.(Phe167Leu) is most probably acting as a modifier of the severity of symptoms if and when affected phenotypes are generated from co-existing pathogenic variants.