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

gnomAD frequency: 0.00075  dbSNP: rs149729531

Total submissions: 18

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
Illumina Laboratory Services, Illumina	RCV000343760	SCV000467106	benign	Batten-Turner congenital myopathy	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
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 Inc	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.
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.
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.