Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001296750 | SCV001485724 | pathogenic | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2023-11-21 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 229 of the CLCN1 protein (p.Val229Met). This variant is present in population databases (rs761601545, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 26260254; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1000597). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV003145518 | SCV003830738 | likely pathogenic | not provided | 2023-06-30 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004799641 | SCV004038268 | likely pathogenic | Congenital myotonia, autosomal recessive form | 2024-09-10 | criteria provided, single submitter | clinical testing | Variant summary: CLCN1 c.685G>A (p.Val229Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251050 control chromosomes. c.685G>A has been reported in the literature in at least two compound heterozygous siblings and an unrelated homozygous individual affected with autosomal recessive Myotonia congenita (e.g. Liu_2015, Gorukmez_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26260254, 36964972). ClinVar contains an entry for this variant (Variation ID: 1000597). Based on the evidence outlined above, the variant was classified as likely pathogenic. |