Submissions for variant NM_173660.5(DOK7):c.1263del (p.Ser422fs)

dbSNP: rs606231129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383180	SCV001582249	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 10	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser422Hisfs*34) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 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 individuals with clinical features of congenital myasthenic syndrome and/or developmental delay and exercise intolerance (PMID: 18626973, 23219351, 25326637, 31618753). ClinVar contains an entry for this variant (Variation ID: 242521). This variant disrupts the C-terminus of the DOK7 protein. Other variant(s) that disrupt this region (p.Gly479Hisfs*13, p.Gln460*) have been observed in individuals with DOK7-related conditions (PMID: 20012313, 20458068). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001582795	SCV001812353	pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 83 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18626973, 23219351, 22661499, 31618753)
Revvity Omics, Revvity	RCV001582795	SCV002021750	pathogenic	not provided	2020-03-17	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288927	SCV002581224	likely pathogenic	Congenital myasthenic syndrome 10	2021-11-08	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV002288927	SCV003841762	pathogenic	Congenital myasthenic syndrome 10	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 31618753). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000242521 / PMID: 18626973). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV003469177	SCV004194040	pathogenic	Fetal akinesia deformation sequence 3	2024-02-10	criteria provided, single submitter	clinical testing