ClinVar Genomic variation as it relates to human health
NM_012193.4(FZD4):c.313A>G (p.Met105Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012193.4(FZD4):c.313A>G (p.Met105Val)
Variation ID: 224624 Accession: VCV000224624.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q14.2 11: 86952443 (GRCh38) [ NCBI UCSC ] 11: 86663485 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2016 Mar 16, 2024 Feb 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012193.4:c.313A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036325.2:p.Met105Val missense NR_120591.3:n.1806T>C non-coding transcript variant NR_120592.2:n.1555T>C non-coding transcript variant NC_000011.10:g.86952443T>C NC_000011.9:g.86663485T>C NG_011752.1:g.7949A>G Q9ULV1:p.Met105Val - Protein change
- M105V
- Other names
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- Canonical SPDI
- NC_000011.10:86952442:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FZD4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
75 | 492 | |
PRSS23 | - | - |
GRCh38 GRCh37 |
21 | - |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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- | RCV000210241.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 11, 2023 | RCV000255410.9 | |
Pathogenic (2) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763285.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2018 | RCV000825614.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 5, 2019 | RCV001073502.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2019 | RCV001002698.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 21, 2024 | RCV003907780.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Exudative vitreoretinopathy 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893932.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Familial exudative vitreoretinopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000966966.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Atrophia bulborum hereditaria
Affected status: yes
Allele origin:
germline
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Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV001156400.1
First in ClinVar: Feb 15, 2020 Last updated: Feb 15, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Retinal dysplasia (present) , Retinal detachment (present) , Blindness (present) , Sensorineural hearing impairment (present) , Seizures (present) , Aggressive behaviour (present)
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Pathogenic
(Apr 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Retinal dystrophy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001239045.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000321680.9
First in ClinVar: Oct 09, 2016 Last updated: Nov 25, 2023 |
Comment:
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; … (more)
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) (less)
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Pathogenic
(Sep 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001589663.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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FZD4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004719713.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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://0-www-ncbi-nlm-nih-gov.brum.beds.ac.uk/clinvar/variation/224624/). Given all the evidence, we interpret this variant as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Exudative retinopathy
Familial exudative vitreoretinopathy
Affected status: yes
Allele origin:
germline
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Laboratory of Human Molecular Genetics, Department of Medical Research, Taipei Veterans General Hospital
Accession: SCV000266327.1
First in ClinVar: Mar 24, 2016 Last updated: Mar 24, 2016 |
Number of individuals with the variant: 3
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Exudative vitreoretinopathy 1
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760286.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Early vitrectomy to reverse macular dragging in a one-month-old boy with familial exudative vitreoretinopathy. | Iwata A | American journal of ophthalmology case reports | 2019 | PMID: 31294129 |
Spectrum of Variants in 389 Chinese Probands With Familial Exudative Vitreoretinopathy. | Li JK | Investigative ophthalmology & visual science | 2018 | PMID: 30452590 |
Mutation spectrum of the FZD-4, TSPAN12 AND ZNF408 genes in Indian FEVR patients. | Musada GR | BMC ophthalmology | 2016 | PMID: 27316669 |
Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients. | Salvo J | Investigative ophthalmology & visual science | 2015 | PMID: 25711638 |
Identification of the cellular mechanisms that modulate trafficking of frizzled family receptor 4 (FZD4) missense mutants associated with familial exudative vitreoretinopathy. | Milhem RM | Investigative ophthalmology & visual science | 2014 | PMID: 24744206 |
Novel frizzled-4 gene mutations in chinese patients with familial exudative vitreoretinopathy. | Jia LY | Archives of ophthalmology (Chicago, Ill. : 1960) | 2010 | PMID: 20938005 |
Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. | Nikopoulos K | Human mutation | 2010 | PMID: 20340138 |
Moderate reduction of Norrin signaling activity associated with the causative missense mutations identified in patients with familial exudative vitreoretinopathy. | Qin M | Human genetics | 2008 | PMID: 17955262 |
Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. | Xu Q | Cell | 2004 | PMID: 15035989 |
Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. | Kondo H | The British journal of ophthalmology | 2003 | PMID: 14507768 |
Text-mined citations for rs80358284 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.