Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV001644600 | SCV000612770 | uncertain significance | not provided | 2021-04-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000706509 | SCV000835564 | uncertain significance | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 583 of the CLCN1 protein (p.Gln583Arg). This variant is present in population databases (rs747895358, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive CLCN1-related disease (PMID: 34529042; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447057). 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. 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. |
| Revvity Omics, |
RCV001644600 | SCV003830744 | uncertain significance | not provided | 2021-05-20 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323582 | SCV004028993 | uncertain significance | not specified | 2023-07-27 | criteria provided, single submitter | clinical testing | Variant summary: CLCN1 c.1748A>G (p.Gln583Arg) 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 1.6e-05 in 251184 control chromosomes (i.e., 4 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1748A>G has been reported in the literature in at least two compound heterozygous individuals affected with Myotonia congenita (e.g., Suetterlin_2022); segregation analysis confirmed a recessive pattern of inheritance in at least one of these individuals. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant affects the voltage dependence of activation in a manner in agreement with the variant being pathogenic in a recessive, but not a dominant setting (e.g., Suetterlin_2022). However, these findings do not allow convincing conclusions about the variant effect. The following publication was ascertained in the context of this evaluation (PMID: 34529042). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |