ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1649C>T (p.Thr550Met) (rs762754992)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000194136 SCV000243885 pathogenic Myotonia congenita 2015-08-06 no assertion criteria provided literature only
Invitae RCV000793565 SCV000932923 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 550 of the CLCN1 protein (p.Thr550Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs762754992, ExAC 0.01%). This variant has been reported to segregate with autosomal dominant myotonia congenita in a family (PMID: 12390967) and has been observed in affected individuals in the heterozygous state (PMID: 24530047, Invitae). In addition, this variant has been observed in combination with another CLCN1 variant in several individuals affected with autosomal recessive myotonia congenita (PMID: 23113340, 25438602).  ClinVar contains an entry for this variant (Variation ID: 208084). Experimental studies have shown that this missense change affects the gating of CLC-1 channels (PMID: 12390967). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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