Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000517112 | SCV000612792 | likely pathogenic | not provided | 2017-03-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000545021 | SCV000636338 | pathogenic | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2023-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the CLCN1 protein (p.Leu198Val). This variant is present in population databases (rs80356685, gnomAD 0.008%). This missense change has been observed in individuals with autosomal dominant myotonia congenita (PMID: 15241802, 23113340; Invitae). ClinVar contains an entry for this variant (Variation ID: 21046). 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: 15241802). This variant disrupts the p.Leu198 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 23739125), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000517112 | SCV005080469 | likely pathogenic | not provided | 2024-01-10 | criteria provided, single submitter | clinical testing | Observed in an individual with myotonia and was found to be inherited from an unaffected parent (PMID: 15241802); Observed in two families with myotonia and noted to have autosomal dominant inheritance (PMID: 23113340); Reported as a variant of uncertain significance in an individual with myotonia (PMID: 32670189); Published functional studies show that L198V alters channel dynamics and impacts dimerization with wildtype channels, exerting a dominant negative effect on channel gating (PMID: 15241802); Published functional studies show that L198V alters channel dynamics; however, the alteration was described as not significant enough to be considered dominant negative and was classified as having recessive functional features (PMID: 34529042); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20398785, 15786415, 34529042, 23113340, 32670189, 15241802) |