ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In our internal patient population, this variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. This variant has been seen heterozygous and compound heterozygous in at least one individual with clinical features associated with this gene. This variant is also referred to as c.434-5_434-4insGCA in published literature. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing.

Variant summary: CLCN1 c.434-2_434dupAGC is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251114 control chromosomes. c.434-2_434dupAGC has been reported in the literature in individuals affected with Myotonia congenita. 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: 31544778, 34529042). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This variant, c.434-2_434dup, results in the insertion of 1 amino acid(s) of the CLCN1 protein (p.Ala145dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753470655, gnomAD 0.007%). This variant has been observed in individual(s) with clinical features of autosomal recessive myotonia congenita (PMID: 31544778; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 31544778); however, the role of the variant in this condition is currently unclear. This variant is also known as c.434-5_434-4insGCA. ClinVar contains an entry for this variant (Variation ID: 462844). 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.

Observed multiple times with a pathogenic variant in unrelated patients with myotonia congenita in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 34529042); Observed as heterozygous variant in one patient with muscular hypertrophy and warm-up phenomenon and also observed with a pathogenic variant in a patient with myotonic runs on EMG in published literature. It is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes. (PMID: 31544778); Canonical splice site variant with an unclear effect on protein function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.434-5insGCA; This variant is associated with the following publications: (PMID: 31544778, 34529042)