ClinVar Miner

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

dbSNP: rs797045032
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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 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 2021-12-03 criteria provided, single submitter clinical testing Published electrophysiological studies in HEK293 cells showed a dramatic positive shift in voltage-dependent activation and highly reduced chloride currents (Desaphy et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633545, 23739125, 32117024, 32664137, 23933576, 22921319, 23113340, 24349310, 19697366, 22521272, 29606556, 32558419, 33013670, 32655465, 29809153)
Athena Diagnostics Inc RCV000489144 SCV000612791 pathogenic not provided 2022-01-11 criteria provided, single submitter clinical testing This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22921319, 23113340), however, it has also been reported in individuals with autosomal dominant myotonia congenita (PMID: 23113340, 19697366, 22921319). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair channel function by reducing permeability, current density and affecting channel deactivation properties (PMID: 22521272, 23933576).
Invitae RCV000530150 SCV000649786 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the CLCN1 protein (p.Gly190Ser). This variant is present in population databases (rs797045032, gnomAD 0.004%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive myotonia congenita (PMID: 19697366, 21221019, 22521272, 22921319, 23739125, 24349310, 26007199). It has also been observed to segregate with disease in related individuals; 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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22521272, 23933576). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga) 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
Revvity Omics, Revvity Omics RCV000489144 SCV002017368 pathogenic not provided 2023-08-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000489144 SCV002563982 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002288796 SCV002580350 pathogenic Congenital myotonia, autosomal dominant form 2021-09-27 criteria provided, single submitter clinical testing

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