Submissions for variant NM_016373.4(WWOX):c.214C>T (p.Gln72Ter)

dbSNP: rs201008667

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521914	SCV000618390	likely pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	Reported as p.Q72X in a patient excluded from a WOREE cohort, as the patient had a mild phenotype and the variant was seen in trans with a missense variant that only affects a non-RefSeq WWOX protein (Piard et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24456803, 30356099, 31589614, 27535533, 31440721)
Invitae	RCV000798699	SCV000938326	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln72*) in the WWOX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WWOX are known to be pathogenic (PMID: 24456803, 25411445). This variant is present in population databases (rs201008667, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 449920). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002527597	SCV003761360	pathogenic	Developmental and epileptic encephalopathy, 28	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Gln72Ter variant in WWOX was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000016.10:g.78424965T>C), in one individual with epilepsy, global developmental delay, and hypoplasia of the corpus callosum. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (NC_000016.10:g.78424965T>C). The p.Gln72Ter variant in WWOX has been previously reported in 2 unrelated individuals with developmental and epileptic encephalopathy 28 (PMID: 33916893) but has been identified in 0.008% (9/113214) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201008667). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These two affected individuals were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 33916893, ClinVar Variation ID: 584160, 830545), which increases the likelihood that the p.Gln72Ter variant in WWOX is pathogenic. This variant has also been reported in ClinVar (Variation ID: 449920) and has been interpreted as pathogenic by Invitae and as likely pathogenic by GeneDx. This nonsense variant leads to a premature termination codon at position 72, which is predicted to lead to a truncated or absent protein. Loss of function of the WWOX gene is strongly associated to autosomal recessive developmental and epileptic encephalopathy 28. In summary, this variant meets criteria to be classified as pathogenic for developmental and epileptic encephalopathy 28. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_Strong (Richards 2015).