ClinVar Miner

Submissions for variant NM_173660.5(DOK7):c.514G>A (p.Gly172Arg)

gnomAD frequency: 0.00001  dbSNP: rs768892432
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000679966 SCV000807400 pathogenic Fetal akinesia deformation sequence 1 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic mutation in a fetal demise with fetal dyskinesia.
Clinical Genetics and Genomics, Karolinska University Hospital RCV001269756 SCV001449998 likely pathogenic not provided 2018-01-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001390615 SCV001592404 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10 2023-08-17 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 172 of the DOK7 protein (p.Gly172Arg). This variant is present in population databases (rs768892432, gnomAD 0.006%). This missense change has been observed in individual(s) with DOK7-related conditions (PMID: 20012313, 28716243, 30266093). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 560992). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003459655 SCV004194044 pathogenic Fetal akinesia deformation sequence 3 2023-05-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV004760698 SCV004234393 likely pathogenic Congenital myasthenic syndrome 10 2024-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004768550 SCV005380822 likely pathogenic Congenital myasthenic syndrome 2024-08-08 criteria provided, single submitter clinical testing Variant summary: DOK7 c.514G>A (p.Gly172Arg) results in a non-conservative amino acid change located in the IRS-type PTB domain (IPR002404) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250644 control chromosomes. c.514G>A has been reported in the literature in compound heterozygous individuals affected with Congenital Myasthenic Syndrome and in one family, this variant has been shown to segregate with disease (Ben Ammar_2010, Gaist_2017, Normand_2018, Ek_2023). 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: 20012313, 37273706, 28716243, 30266093). ClinVar contains an entry for this variant (Variation ID: 560992). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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