Submissions for variant NM_016373.4(WWOX):c.605+5G>A

gnomAD frequency: 0.00001  dbSNP: rs1039151413

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522383	SCV000619192	likely pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The c.605+5 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.605+5 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.605+5 G>A destroys the natural donor site of intron 6 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000703936	SCV000832864	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2022-03-10	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the WWOX gene. It does not directly change the encoded amino acid sequence of the WWOX protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of WWOX-related conditions (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: 450592). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000850619	SCV000992852	uncertain significance	Autosomal recessive spinocerebellar ataxia 12; Developmental and epileptic encephalopathy, 28	2017-12-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000522383	SCV003802841	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	The WWOX c.605+5G>A variant occurs in a splice donor region and results in the substitution of a guanine at nucleotide position c.605+5 with an adenine. The c.605+5G>A variant is reported as an ostensibly disease-causing variant in a study describing outcomes of exome sequencing data reanalysis in a large cohort; however, specific details about the relevant case are unavailable (PMID: 31216405). Additionally, ClinVar submissions from clinical laboratories report detecting the c.605+5G>A variant in individuals with features consistent with WWOX-associated phenotypes; however, this data is currently unpublished and unavailable for review (Accession VCV000450592.4; PMID: 29165669) This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000087 in the Latino/Admixed American population (version 2.1.1). In silico prediction tools suggest that this variant may result in splice defects; however, this has not been verified experimentally. Based on the available evidence, the c.605+5G>A variant is classified as a variant of uncertain significance for developmental and epileptic encephalopathy.
Baylor Genetics	RCV003152608	SCV003841209	likely pathogenic	Developmental and epileptic encephalopathy, 28		criteria provided, single submitter	clinical testing