Submissions for variant NM_016373.4(WWOX):c.1043del (p.Phe348fs)

dbSNP: rs1064795117

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484968	SCV000570601	likely pathogenic	not provided	2019-12-06	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant on the opposite allele (in trans) in a patient referred for genetic testing at GeneDx with seizures, cortical visual impairment, and global developmental delay; Observed in a patient with seizures, epileptic encephalopathy, spasticity, blindness, and developmental regression referred for genetic testing at GeneDx in the presence of a second pathogenic WWOX variant; Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 67 amino acids are lost and replaced with 56 incorrect amino acids; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381454	SCV001579837	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the WWOX protein in which other variant(s) (p.Gly372*) have been determined to be pathogenic (PMID: 31780880; 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. ClinVar contains an entry for this variant (Variation ID: 421407). This premature translational stop signal has been observed in individual(s) with clinical features of epileptic encephalopathy (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Phe348Serfs*57) in the WWOX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acid(s) of the WWOX protein.