ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1672C>T (p.Pro558Ser)

dbSNP: rs1586510615
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000823200 SCV000964049 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the CLCN1 protein (p.Pro558Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 23933576, 34529042). ClinVar contains an entry for this variant (Variation ID: 665000). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 23933576). 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.
GeneDx RCV004768705 SCV005377904 uncertain significance not provided 2024-04-17 criteria provided, single submitter clinical testing Reported previously in association with myotonia congenita; some of these patients also harbored other variants although phase was unknown (PMID: 22109722, 23810313, 34529042); Published functional studies using Xenopus oocytes showed that this variant had reduced current amplitude and displayed recessive functional features (PMID: 34529042); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23933576, 27066513, 23810313, 34529042, 22109722)

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