ClinVar Miner

Submissions for variant NM_173660.5(DOK7):c.331+1G>T

gnomAD frequency: 0.00001  dbSNP: rs1349476281
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520261 SCV000617811 pathogenic not provided 2022-12-02 criteria provided, single submitter clinical testing Reported in a patient with congenital myasthenia who also harbored the common c.1124_1127dupTGCC variant (Selcen et al., 2008); Canonical splice site variant expected to result in aberrant splicing; Published functional studies demonstrate a damaging effect (Selcen et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22482962, 18626973, 19261599)
Genetic Services Laboratory, University of Chicago RCV000520261 SCV002070514 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003403229 SCV004104040 pathogenic DOK7-related disorder 2023-07-20 criteria provided, single submitter clinical testing The DOK7 c.331+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in patients with autosomal recessive congenital myasthenic syndrome (Selcen et al. 2008. PubMed ID: 18626973) and fetal akinesia deformation sequence (Vogt et al. 2009. PubMed ID: 19261599). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-3475364-G-T). In summary, the c.331+1G>T variant is categorized as pathogenic for recessive DOK7-related disorders.
Baylor Genetics RCV000767366 SCV004194026 pathogenic Fetal akinesia deformation sequence 3 2023-09-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479149 SCV004223773 pathogenic Congenital myasthenic syndrome 2023-11-13 criteria provided, single submitter clinical testing Variant summary: DOK7 c.331+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to exon skipping. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping exon 3 and the resultant in-frame muatant DOK7 failed to phosphorylate MuSK in HEK cells (Selcen_2008). The variant allele was found at a frequency of 1.1e-05 in 181712 control chromosomes. c.331+1G>T has been reported in the literature in multiple individuals affected with lethal Fetal akinesia deformation sequence syndrome or Myasthenic Syndrome (examples, Vogt_2009, Selcen_2008). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18626973, 19261599). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV003766941 SCV004591132 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10 2023-03-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the DOK7 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DOK7 are known to be pathogenic (PMID: 16794080, 16917026, 18626973, 19261599). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 18626973). Experimental studies have shown that disruption of this splice site affects DOK7 function (PMID: 18626973). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 449547). Disruption of this splice site has been observed in individual(s) with DOK7-related conditions (PMID: 18626973, 19261599). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.
OMIM RCV000001343 SCV000021493 pathogenic Congenital myasthenic syndrome 10 2009-05-01 no assertion criteria provided literature only
OMIM RCV000767366 SCV000897937 pathogenic Fetal akinesia deformation sequence 3 2009-05-01 no assertion criteria provided literature only

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