Submissions for variant NM_000083.3(CLCN1):c.1445G>A (p.Gly482Glu)

dbSNP: rs1380726444

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685629	SCV000813115	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 482 of the CLCN1 protein (p.Gly482Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita and/or nondystrophic myotonia (PMID: 24349310, 33263785; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 565939). 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%. This variant disrupts the p.Gly482 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22346025, 25065301; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001756153	SCV001986271	likely pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Observed in unrelated individuals with myotonia congenita as heterozygous, homozygous, and/or with a second CLCN1 variant (Vereb et al., 2021; Gilitwala et al., 2023; Sklov et al., 2013); 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: 24349310, 37489215, 33263785)
Revvity Omics, Revvity	RCV001756153	SCV003830764	uncertain significance	not provided	2020-02-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001756153	SCV004229535	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with apparently autosomal dominant myotonia congenita (PMID: 33263785) and at least one individual with clinical features consistent with autosomal recessive myotonia congenita. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.