Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Kariminejad - |
RCV001836882 | SCV000927074 | likely pathogenic | Abnormality of the musculature | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001063540 | SCV001228390 | pathogenic | Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change affects codon 258 of the CLCN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CLCN1 protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs770605959, gnomAD 0.0009%). This variant has been observed in individuals with autosomal recessive myotonia congenita (PMID: 28427807; Invitae). This variant is also known as c.861G>A. ClinVar contains an entry for this variant (Variation ID: 636302). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Laboratory of Medical Genetics, |
RCV003883164 | SCV004697568 | likely pathogenic | Congenital myotonia, autosomal recessive form | 2024-02-20 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003883164 | SCV005186024 | pathogenic | Congenital myotonia, autosomal recessive form | 2024-05-02 | criteria provided, single submitter | clinical testing | Variant summary: CLCN1 c.774G>A (p.Glu258Glu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251430 control chromosomes (gnomAD). c.774G>A has been reported in the literature in multiple individuals affected with Myotonia congenita (e.g. Ferradini_2017, Stunnenberg_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28427807, 29606556). ClinVar contains an entry for this variant (Variation ID: 636302). Based on the evidence outlined above, the variant was classified as pathogenic. |