ClinVar Miner

Submissions for variant NM_000083.2(CLCN1):c.1444G>A (p.Gly482Arg) (rs746125212)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657922 SCV000779689 likely pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing The G482R variant was initially reported in two unrelated patients with clinical features suggestive of the autosomal recessive form of myotonia congenita (Becker disease); however, a second CLCN1 variant was not reported for these individuals (Meyer-Kleine e al., 1995). Subsequently, G482R was identified in another patient with myotonia congenita, although a second CLCN1 variant was not identified and G482R was found to be inherited from an unaffected father (Jou et al., 2004). The G482R variant was observed in two additional patients with myotonia congenita, one who did not harbor a second CLCN1 variant and one who did harbor a second CLCN1 variant (Lo Monaco et al., 2015). Electrophysiological analysis of Xenopus oocytes demonstrate G482R results in loss of CLCN1 channel function (Lin et al., 2006). The G482R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, a different missense variant at the same position (G482E) has been reported in an individual with myotonia congenita who harbored a second CLCN1 variant (Skálová et al., 2013).
OMIM RCV000019088 SCV000039376 pathogenic Congenital myotonia, autosomal recessive form 2013-10-07 no assertion criteria provided literature only

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