ClinVar Miner

Submissions for variant NM_012193.4(FZD4):c.313A>G (p.Met105Val) (rs80358284)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255410 SCV000321680 pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing The M105V missense variant in the FZD4 gene has been reported previously in association with familial exudative vitreoretinopathy (FEVR) (Kondo et al., 2003; Jia et al., 2010). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M105V variant is located in the extracellular cysteine rich domain, which is a critical binding site for Wnt proteins (Toomes et al., 2004).
Fulgent Genetics,Fulgent Genetics RCV000763285 SCV000893932 pathogenic Exudative vitreoretinopathy 1 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825614 SCV000966966 pathogenic Familial exudative vitreoretinopathy 2018-08-01 criteria provided, single submitter clinical testing The p.Met105Val variant in FZD4 has been reported in at least 8 individuals with familial exudative vitreoretinopathy (FEVR) and segregated with disease in 4 af fected relatives from multiple families (Jia 2010, Kondo 2003, Musada 2016, Salv o 2015, Xu 2004). This variant has also been identified in 3/33580 Latino chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs80358284). In vitro functional studies provide some evidence that th e p.Met105Val variant may impact protein function (Milhem 2014, Xu 2004). FEVR s hows highly variable expressivity and reduced penetrance. Individuals carrying p athogenic variants usually show peripheral retinal avascularity; however, clinic al presentation ranges from asymptomatic to early childhood blindness. In summar y, this variant meets criteria to be classified as pathogenic for FEVR in an aut osomal dominant based upon presence in affected individuals, segregation studies , and functional evidence. ACMG/AMP Criteria applied: PS4; PM2; PS3_Moderate; PP 1_Supporting; PP3.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV001002698 SCV001156400 pathogenic Atrophia bulborum hereditaria 2019-02-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073502 SCV001239045 pathogenic Retinal dystrophy 2019-04-05 criteria provided, single submitter clinical testing
Laboratory of Human Molecular Genetics, Department of Medical Research,Taipei Veterans General Hospital RCV000210241 SCV000266327 pathogenic Exudative retinopathy; Familial exudative vitreoretinopathy no assertion criteria provided research

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