ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1231G>T (p.Gly411Cys) (rs756199349)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494058 SCV000582281 uncertain significance not provided 2017-12-22 criteria provided, single submitter clinical testing The G411C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G411C variant is not observed in large population cohorts (Lek et al., 2016). The G411C 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. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with myotonia (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000536398 SCV000636301 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 411 of the CLCN1 protein (p.Gly411Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs756199349, ExAC 0.001%). This variant has not been reported in the literature in individuals with CLCN1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000494058 SCV001155293 likely pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing

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