ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1655A>G (p.Gln552Arg) (rs80356696)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000498537 SCV000612769 pathogenic not provided 2017-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000498537 SCV000589659 likely pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing The Q552R variant was previously reported as a heterozygous variant in a family with mild to moderate myotonia of bulbar muscles and miminal myotonia of arm and leg muscles (Lehmann-Horn et al., 1995). Functional studies indicate Q552R results in a weak dominant negative effect and alters channel gating properties (Ryan et al., 2002). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q552R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (E548K; T550M/R; G551D; I553F; H555N; I556N) have been reported in the Human Gene Mutation Database in association with myotonia congenita (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
GeneReviews RCV000020103 SCV000040423 pathologic Myotonia congenita 2011-04-12 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000685420 SCV000812899 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 552 of the CLCN1 protein (p.Gln552Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant myotonia levior in a family (PMID: 7581380). ClinVar contains an entry for this variant (Variation ID: 17538). Experimental studies have shown that expression of this missense change in Xenopus oocytes, as well as cultured cells, results in altered gating properties and reduced current (PMID: 8845168, 12456818). 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.
OMIM RCV000019090 SCV000039378 pathogenic Myotonia levior 2002-12-01 no assertion criteria provided literature only

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