Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000533620 | SCV000640976 | likely pathogenic | Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10 | 2016-12-03 | criteria provided, single submitter | clinical testing | This sequence change inserts 1 nucleotide in exon 7 of the DOK7 mRNA (c.957dupC), causing a frameshift at codon 320. This creates a premature translational stop signal in the last exon of the DOK7 mRNA (p.Lys320Glnfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 185 amino acids of the DOK7 protein. While this particular variant has not been reported in the literature, truncating variants in DOK7 are known to be pathogenic (PMID: 16917026) A different truncation downstream of this variant (p.1124_1127dupTGCC) has been determined to be pathogenic (PMID: 16917026, 23657916). This suggests that deletion of this region of the DOK7 protein is causative of disease. In summary, this variant is a rare duplication that is expected to disrupt the last 185 amino acids of the DOK7 protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Mendelics | RCV000987398 | SCV001136687 | likely pathogenic | Fetal akinesia deformation sequence 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230537 | SCV003928727 | pathogenic | Congenital myasthenic syndrome | 2023-04-24 | criteria provided, single submitter | clinical testing | Variant summary: DOK7 c.957dupC (p.Lys320GlnfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1263dupC). The variant allele was found at a frequency of 2.9e-05 in 138024 control chromosomes. To our knowledge, no occurrence of c.957dupC in individuals affected with Congenital Myasthenic Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003470751 | SCV004194017 | likely pathogenic | Fetal akinesia deformation sequence 3 | 2024-01-06 | criteria provided, single submitter | clinical testing |