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

gnomAD frequency: 0.00004  dbSNP: rs80358284

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255410	SCV000321680	pathogenic	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Observed frequently in unrelated patients from different ethnic backgrounds with familial exudative vitreoretinopathy in the published literature (Kondo et al., 2003; Toomes et al., 2004; Yang et al., 2012; Seo et al., 2015; Musada et al., 2016; Li et al., 2018; Chen et al., 2019; Jiman et al., 2020); Published functional studies demonstrate defective protein trafficking compared to wild type (Milhem et al., 2014); This variant is associated with the following publications: (PMID: 31836858, 17955262, 30097784, 30452590, 26747767, 31237656, 30910914, 31294129, 31987760, 25711638, 14507768, 27316669, 15223780, 20938005, 32884843, 31827910, 31892318, 33090715, 35328049, 35876299, 34758253, 24744206, 34860240, 23077402, 26244290, 35394490)
Fulgent Genetics, Fulgent Genetics	RCV000763285	SCV000893932	pathogenic	Exudative vitreoretinopathy 1	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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
Invitae	RCV000255410	SCV001589663	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 105 of the FZD4 protein (p.Met105Val). This variant is present in population databases (rs80358284, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of familial exudative vitreoretinopathy (PMID: 14507768, 30452590, 31294129). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224624). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FZD4 protein function. Experimental studies have shown that this missense change affects FZD4 function (PMID: 17955262, 24744206). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
PreventionGenetics, part of Exact Sciences	RCV003907780	SCV004719713	pathogenic	FZD4-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The FZD4 c.313A>G variant is predicted to result in the amino acid substitution p.Met105Val. This variant has been reported many times as causative for autosomal dominant familial exudative vitreoretinopathy (see for examples Kondo et al. 2003. PubMed ID: 14507768; Chen. 2019. PubMed ID: 31237656). Alternate substitutions of this amino acid (p.Met105Thr and p.Met105Arg) have also been reported in individuals with familial exudative vitreoretinopathy (Toomes et al. 2004. PubMed ID: 15223780; Han et al. 2020. PubMed ID: 32420371). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/224624/). Given all the evidence, we interpret this variant as pathogenic.
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
Genomics England Pilot Project, Genomics England	RCV000763285	SCV001760286	likely pathogenic	Exudative vitreoretinopathy 1		no assertion criteria provided	clinical testing