Submissions for variant NM_016373.4(WWOX):c.766A>T (p.Ile256Phe)

dbSNP: rs1023419687

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658284	SCV000780055	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the WWOX gene. The I256F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I256F variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the I256F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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	RCV001038611	SCV001202090	uncertain significance	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2019-02-24	criteria provided, single submitter	clinical testing	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. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces isoleucine with phenylalanine at codon 256 of the WWOX protein (p.Ile256Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with WWOX-related conditions. ClinVar contains an entry for this variant (Variation ID: 546413).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193911	SCV001363084	uncertain significance	not specified	2019-09-05	criteria provided, single submitter	clinical testing	Variant summary: WWOX c.766A>T (p.Ile256Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249542 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.766A>T in individuals affected with Early Infantile Epileptic Encephalopathy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.