ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.568_569delinsTC (p.Gly190Ser) (rs797045032)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191069 SCV000245461 likely pathogenic Congenital myotonia, autosomal recessive form 2013-11-26 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory with a known pathogenic missense variant (F167L; 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.
GeneDx RCV000489144 SCV000577243 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The c.568_569delGGinsTC variant in the CLCN1 gene has been previously reported in thehomozygous, compound heterozygous, and heterozygous states in association with myotoniacongenita (Shalata et al., 2010; Ulzi et al., 2012). Homozygotes and compound heterozygotes were moderately to severely affected with disease onset in the first decade of life. Heterozygotes were asymptomatic or mildly affected and only had limb contraction involvement (Shalata et al., 2010). The c.568_569delGGinsTC variant causes an in-frame replacement, changing a Glycine residue at codon 190 to a Serine residue, denoted p.Gly190Ser. The c.568_569delGGinsTC variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies revealed that patch clamp analysis of the c.568_569delGGinsTC variant in HEK293 cells showed dramatic positive shift of activation voltage-dependence resulting in almost no detectable chloride currents (Desaphy et al., 2013). The c.568_569delGGinsTC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.568_569delGGinsTC as a pathogenic variant.
Athena Diagnostics Inc RCV000489144 SCV000612791 pathogenic not provided 2015-11-03 criteria provided, single submitter clinical testing
Invitae RCV000530150 SCV000649786 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2020-10-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 190 of the CLCN1 protein (p.Gly190Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the heterozygous, homozygous and compound heterozygous state in many individuals affected myotonia congenita (PMID: 19697366, 22921319, 22521272, 23739125, 21221019, 24349310, 26007199). It has been shown to co-segregate with disease in two families; in the heterozygous state this variant was reported to be incompletely penetrant and in the homozygous state it was reported to cause a more severe phenotype (PMID: 19697366, 22921319). ClinVar contains an entry for this variant (Variation ID: 209139). Experimental studies have shown that this missense change alters the voltage-dependent activation kinetics of the CLCN1 channel (PMID: 22521272, 23933576). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000489144 SCV000704674 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626583 SCV000747284 pathogenic Myocardial infarction; Headache; Rigidity; Vertigo; Myotonia of the upper limb; EMG: myotonic discharges 2017-01-01 criteria provided, single submitter clinical testing

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