Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000692856 | SCV000820701 | pathogenic | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 137 of the CLCN1 protein (p.Tyr137Asp). This variant is present in population databases (rs748639603, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22094069, 26502825). ClinVar contains an entry for this variant (Variation ID: 571653). 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. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22094069, 26502825). For these reasons, this variant has been classified as Pathogenic. |
Athena Diagnostics Inc | RCV000991825 | SCV001143598 | pathogenic | not provided | 2022-03-29 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with autosomal recessive myotonia congenita (PMID: 22094069, 26502825). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in altered channel activity (PMID: 22094069, 26502825). |
Gene |
RCV000991825 | SCV001986270 | pathogenic | not provided | 2021-03-02 | criteria provided, single submitter | clinical testing | Reported in the heterozygous state, without a second variant, in a patient with neonatal onset of severe muscle stiffness and respiratory failure who also harbored an apparently de novo variant in the SCN4A gene which the authors deemed explanative of the patient's phenotype (Pechmann et al., 2019); Published functional studies demonstrate a damaging effect with a deleterious effect on channel function and impaired membrane trafficking (Mazon et al., 2012; Ronstedt et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32117034, 22094069, 23152584, 26502825, 32670189, 31589614, 32528171, 31732390) |
Practice for Gait Abnormalities, |
RCV003319405 | SCV004023402 | likely pathogenic | Tip-toe gait | 2021-09-20 | no assertion criteria provided | clinical testing |