Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000516411 | SCV000612751 | pathogenic | not provided | 2014-05-12 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000527543 | SCV000636289 | pathogenic | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 355 of the CLCN1 protein (p.Gly355Arg). This variant is present in population databases (rs767000881, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 19949657, 20181190, 21221019, 28427807; Invitae). ClinVar contains an entry for this variant (Variation ID: 447043). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 23933576). This variant disrupts the p.Gly355 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 18337100), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV002227480 | SCV002507087 | likely pathogenic | Congenital myotonia, autosomal recessive form | 2022-05-04 | criteria provided, single submitter | curation | The homozygous p.Gly355Arg variant in CLCN1 was identified by our study in 2 siblings with autosomal recessive myotonia congenita. The variant has been reported in at least 3 individuals of European and unknown ethnicity with autosomal recessive myotonia congenita (PMID: 20181190, 21221019, 9736066), and has been identified in 0.003% (1/34588) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs767000881). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 447043) as pathogenic by Athena Diagnostics Inc and Invitae. In vitro functional studies provide some evidence that the p.Gly355Arg variant may slightly impact protein function (PMID: 23933576). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 1 affected homozygote, in combination with a reported variant of uncertain significance, and in at least 3 individuals with autosomal recessive myotonia congenita increases the likelihood that the p.Gly355Arg variant is pathogenic (VariationID: 209138; PMID: 9736066, 21221019). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PS3_supporting (Richards 2015). |
| MGZ Medical Genetics Center | RCV002227480 | SCV002579729 | pathogenic | Congenital myotonia, autosomal recessive form | 2021-12-06 | criteria provided, single submitter | clinical testing |