Submissions for variant NM_016373.4(WWOX):c.689A>C (p.Gln230Pro)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004706	SCV001164169	likely pathogenic	Developmental and epileptic encephalopathy, 28	2018-01-05	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV001004706	SCV001432744	pathogenic	Developmental and epileptic encephalopathy, 28	2020-07-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389252	SCV001590541	pathogenic	Developmental and epileptic encephalopathy, 1; Autosomal recessive spinocerebellar ataxia 12	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 230 of the WWOX protein (p.Gln230Pro). This variant is present in population databases (rs199628364, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WWOX-related conditions (PMID: 29808465, 30356099, 30853297). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 813767). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WWOX protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814252	SCV001755656	likely pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001004706	SCV002102973	likely pathogenic	Developmental and epileptic encephalopathy, 28	2021-07-20	criteria provided, single submitter	clinical testing
Mendelics	RCV002249620	SCV002519976	pathogenic	Malignant tumor of esophagus	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV002286798	SCV002577106	pathogenic	not provided	2022-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25411445, 30746283, 33255508, 33916893, 29808465, 35792847, 30853297, 30356099)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307653	SCV002600310	pathogenic	Early Infantile Epileptic Encephalopathy, Autosomal Recessive	2022-10-05	criteria provided, single submitter	clinical testing	Variant summary: WWOX c.689A>C (p.Gln230Pro) results in a non-conservative amino acid change located in the WWOX, classical (c)-like SDR domain (IPR 042732) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249564 control chromosomes. c.689A>C has been reported in the literature in multiple clinically diagnosed individuals affected with Early Infantile Epileptic Encephalopathy, Autosomal Recessive (example Johannsen_2018 and Weisz_2019 etc.). These data indicate that the variant is very likely to be associated with disease. Functional assessment in one homozygous patient revealed normal WWOX transcripts but absent WWOX protein on Western blotting suggesting an impaired protein translation or premature degradation of the misfolded protein after transcription due to quality control mechanisms in the endoplasmic reticulum ( Johannsen_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=3) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505539	SCV002810953	pathogenic	Malignant tumor of esophagus; Autosomal recessive spinocerebellar ataxia 12; Developmental and epileptic encephalopathy, 28	2022-02-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003411947	SCV004114019	likely pathogenic	WWOX-related disorder	2023-07-14	criteria provided, single submitter	clinical testing	The WWOX c.689A>C variant is predicted to result in the amino acid substitution p.Gln230Pro. This variant was reported in both the homozygous and compound heterozygous state in multiple individuals with early-onset epileptic encephalopathy with developmental delay. (Johannsen et al 2018. PubMed ID: 29808465; Weisz-Hubshman M et al 2019. PubMed ID: 30853297; Piard J et al 2018. PubMed ID: 30356099). In vitro functional studies using patient's fibroblast cells that were homozygous for this variant revealed absence of WWOX protein (Johannsen et al 2018. PubMed ID: 29808465). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-78458850-A-C). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV001004706	SCV005049294	pathogenic	Developmental and epileptic encephalopathy, 28	2024-02-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004559832	SCV005049420	pathogenic	Autosomal recessive spinocerebellar ataxia 12	2024-02-18	criteria provided, single submitter	clinical testing