Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ce |
RCV000998934 | SCV001155292 | uncertain significance | not provided | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Neuberg Centre For Genomic Medicine, |
RCV003338899 | SCV004048088 | uncertain significance | Congenital myotonia, autosomal recessive form | criteria provided, single submitter | clinical testing | The missense variant c.983C>T (p.Thr328Ile) has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Thr328Ile variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Thr at position 328 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Thr328Ile in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). | |
| Labcorp Genetics |
RCV005213430 | SCV005851389 | uncertain significance | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2024-08-06 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 328 of the CLCN1 protein (p.Thr328Ile). This variant is present in population databases (rs780421370, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of myotonia congenita (PMID: 33263785, 34529042). ClinVar contains an entry for this variant (Variation ID: 810202). 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: 34529042). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |