ClinVar Miner

Submissions for variant NM_173660.5(DOK7):c.596del (p.Ile199fs)

gnomAD frequency: 0.00001  dbSNP: rs797045528
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000194361 SCV000247196 pathogenic Congenital myasthenic syndrome 10 2015-06-02 criteria provided, single submitter clinical testing
GeneDx RCV003314574 SCV004014516 likely pathogenic not provided 2023-01-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 306 amino acids are replaced with 46 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 18626973)
Baylor Genetics RCV003468882 SCV004194062 pathogenic Fetal akinesia deformation sequence 3 2024-03-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003765216 SCV004569786 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10 2023-08-25 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 210856). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DOK7 protein in which other variant(s) (p.Asp433Argfs*18) have been determined to be pathogenic (PMID: 17439981, 22661499; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that this premature translational stop signal alters DOK7 gene expression (PMID: 18626973). This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 18626973). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs797045528, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Ile199Thrfs*47) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 306 amino acid(s) of the DOK7 protein.

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