Submissions for variant NM_016373.4(WWOX):c.1114G>T (p.Gly372Ter)

dbSNP: rs587777127

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519379	SCV000619193	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The G372X variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G372X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G372X variant is predicted to cause loss of normal protein function through protein truncation; as the last 43 amino acids of the WWOX protein are lost. However, loss of-function variants in nearby residues have not been reported in the Human Gene Mutation Database in association with WWOX-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703935	SCV000832863	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2020-07-21	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the WWOX gene (p.Gly372*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acids of the WWOX protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of epileptic encephalopathy (PMID: 31780880, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 450593). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252153	SCV002523226	likely pathogenic	See cases	2019-08-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2
Illumina Laboratory Services, Illumina	RCV000519379	SCV003802781	likely pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	The WWOX c.1114G>T (p.Gly372Ter) nonsense variant results in the substitution of glycine at amino acid position 372 with a stop codon. This variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay. The p.Gly372Ter variant has been reported in 2 individuals with refractory, syndromic, infantile-onset seizures. Specifically, in a compound heterozygous state with an intragenic deletion in one individual and in a heterozygous state without any candidate variants identified in trans in the second individual (PMID: 31780880; PMID: 31957018). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000029 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence, the c.1114G>T (p.Gly372Ter) variant is classified as likely pathogenic for developmental and epileptic encephalopathy.