Submissions for variant NM_016373.4(WWOX):c.745C>A (p.Arg249Ser)

dbSNP: rs749277249

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523919	SCV000620080	uncertain significance	not provided	2017-08-17	criteria provided, single submitter	clinical testing	The R249S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R249S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R249S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001853656	SCV002198134	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2022-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 249 of the WWOX protein (p.Arg249Ser). This variant is present in population databases (rs749277249, gnomAD 0.004%). 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: 451386). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.