Submissions for variant NM_173660.5(DOK7):c.1143del (p.Glu382fs)

dbSNP: rs606231132

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987399	SCV001136688	pathogenic	Fetal akinesia deformation sequence 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380396	SCV001578459	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu382Serfs*74) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the DOK7 protein. 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. This premature translational stop signal has been observed in individual(s) with clinical features of congenital myasthenic syndrome (PMID: 22661499; Invitae). 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: 802049). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001784485	SCV002021744	pathogenic	not provided	2019-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271602	SCV002555984	pathogenic	Congenital myasthenic syndrome	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: DOK7 c.1143delC (p.Glu382SerfsX74) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.5e-05 in 202922 control chromosomes (gnomAD). c.1143delC has been reported in the literature in homozygous and compound heterozygous individuals with the clinical features of Congenital Myasthenic Syndrome (example Cossins_2012, Ziats_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503146	SCV002809855	pathogenic	Congenital myasthenic syndrome 10; Fetal akinesia deformation sequence 3	2021-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001784485	SCV004040067	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 123 amino acids are replaced with 73 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31618753, 22661499)
Baylor Genetics	RCV003467546	SCV004194063	pathogenic	Fetal akinesia deformation sequence 3	2024-02-10	criteria provided, single submitter	clinical testing