ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.501C>G (p.Phe167Leu) (rs149729531)

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Total submissions: 9
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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 pathogenic Congenital myotonia, autosomal recessive form 2015-07-09 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory with a missense variant (G190S; phase unknown) in a 46-year-old male with heart arrhythmia, hypertrophic cardiomyopathy, neuromuscular disease, EMG evidence of myopathy with myotonic discharges and mild length-dependent neuropathy, poor balance, short stature, scoliosis, small hands.
Illumina Clinical Services Laboratory,Illumina RCV000343760 SCV000467106 benign Myotonia congenita 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 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 167 of the CLCN1 protein (p.Phe167Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs149729531, ExAC 0.2%). This variant has been reported in combination with another CLCN1 variant in individuals affected with autosomal recessive myotonia congenita (Becker disease) (PMID: 24304580, 18337730, 24452722, 22521272, 23113340, 21221019, 27199537, 22094069, 17654559, 22641783). This variant has also been reported in the heterozygous state in affected individuals in whom recessive disease was suspected but no second variant was identified, affected individuals who were found to carry a pathogenic variant in a different gene, as well as in unaffected individuals (PMID: 7874130, 8533761, 22407275, 17654559, 27266866, 27614575, 26510092). Lastly, this variant has been reported to co-occur (likely on the same chromosome) with another common variant of uncertain significance in the CLCN1 gene (PMID: 24349310, 23739125, 24037712, 22094069). The current evidence suggests that this variant appears to only be associated with recessive (and not dominant) CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 209138). Experimental studies report conflicting data regarding the functional effect of this variant on CLCN1 protein channels. In two publications the data suggests that this variant may shift the voltage dependence of channel open probability (PMID: 10690989, 24304580). In contrast, two additional publications report that this variant has little to no effect on kinetics or magnitude of current as compared to wild type CLCN1 channels (PMID: 26510092, 23933576). In summary, this is a missense change that has been reported in affected and unaffected individuals, and has an uncertain effect on protein function. For these reasons, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000711233 SCV000841565 pathogenic not provided 2015-09-21 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000711233 SCV000892807 uncertain significance not provided 2020-02-01 criteria provided, single submitter clinical testing
Mendelics RCV000191070 SCV001137531 uncertain significance Congenital myotonia, autosomal recessive form 2019-05-28 criteria provided, single submitter clinical testing

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