ClinVar Miner

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

gnomAD frequency: 0.00075  dbSNP: rs149729531
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Total submissions: 19
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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.
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.

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