ClinVar Miner

Submissions for variant NM_000083.2(CLCN1):c.937G>A (p.Ala313Thr) (rs80356692)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000224894 SCV000612807 pathogenic not provided 2015-09-17 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224894 SCV000281046 pathogenic not provided 2016-05-09 criteria provided, single submitter clinical testing
GeneReviews RCV000020120 SCV000040440 pathologic Myotonia congenita 2011-04-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000638231 SCV000759717 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2017-08-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 313 of the CLCN1 protein (p.Ala313Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in an autosomal dominant pattern in a family with myotonia congenita; however, in the same family 2 individuals carry other CLCN1 mutations on the opposite chromosome (in trans) and are more severely affected (PMID: 23893571). This variant has also been reported in many individuals/families affected with myotonia congenita in both a recessive and dominant manner with incomplete penetrance (PMID: 9566422, 23225051, 17654559, 17932099, 24037712). ClinVar contains an entry for this variant (Variation ID: 21052). This variant is also known as c.1024G>A in the literature. Experimental studies have shown that this missense change drastically shifted the voltage dependence of ClC-1 to positive potentials, and has dominant negative effect (PMID: 9736777). A different missense substitution at this codon (p.Ala313Val) has been determined to be pathogenic (PMID: 17932099, 24037712). This suggests that the alanine residue is critical for CLCN1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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