ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, 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 Miraca Genetics Laboratories, 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 likely benign Myotonia congenita 2016-06-14 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 2018-12-31 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 the heterozygous or compound heterozygous state in individuals affected with autosomal dominant myotonia congenita (Thomsen disease) or autosomal recessive myotonia congenita (Becker disease) (PMID: 7874130, 23933576, 26510092, 24304580, 18337730, 8533761, 22094069, 17654559, 23739125, 17932099, 24452722, 22109722, 28993909). This variant has also been reported in affected individuals who have 3 variants in the CLCN1 gene (PMID: 24349310, 23739125, 24037712, 22094069). Additionally, this variant has been reported in unaffected individuals (PMID: 27614575, 26510092) and in 1 family this variant did not segregate with disease (PMID: 22094069). 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 rare 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 2018-09-30 criteria provided, single submitter clinical testing

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