ClinVar Genomic variation as it relates to human health

Splice site variant demonstrated to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease (Cossins et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 22661499, 33756069)

Variant summary: DOK7 c.414C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: three predict the variant strengthens a cryptic 3' acceptor site within exon4. At least one publication reports experimental evidence, confirming that this variant affects mRNA splicing, producing a shorter transcript with the deletion of 94 nucleotides at the 5' end of exon 4 (which results in a frameshift at the protein level), in addition to the correctly spliced WT transcript (Cossins_2012). The variant allele was found at a frequency of 1.2e-05 in 250694 control chromosomes (gnomAD. The variant c.414C>T (p.L138L) has been reported in the literature in compound heterozygous individuals affected with Congenital Myasthenic Syndrome (e.g. Cossins_2012, Zhao_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22661499, 33756069). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change affects codon 138 of the DOK7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DOK7 protein. This variant is present in population databases (rs771995943, gnomAD 0.003%). This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 22661499, 33756069). 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: 1703994). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 22661499). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.