Fetal anomalies
Gene: FGD5 Amber List (moderate evidence)I don't know
PMID 41574350 Steffes et al 2026 - identified a de novo NMD predicted FGD5 variant in a 30+3 week old infant with pulmonary artery stenosis and progressive pulmonary arterial hypertension.
PMID 32037394 Reuters et al 2020 - identified a maternally inherited, heterozygous, NMD-predicted variant (p.Glu322*) in a child with pulmonary stenosis, ASD and micrognathia.
PMID 30232381 Reuters et al 2019 - identified an NMD-predicted variant (p.Arg1225*) in an adult with congenital heart disease with no familial segregation information provided.
FGD5 implicated in VEGF pathway and expressed in endothelial cells. pLI score of 1.0. Highest het count in gnomAD for an NMD-predicted PTC variant is 9. Presence of multiple transcripts could contribute to variable expressivity and incomplete penetrance. However, given background prevalence of congenital heart disease, more case-level evidence is required to upgrade this gene-disease association to Green,
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Comment on other evidence:
PMID: 41199744 Liu et al 2025 report a heterozygous FGD5 missense variant c.3233C>A, p.T1078K in a fetus with pulmonary artery stenosis. Variant was inherited from an apparently unaffected mother of East Asian ancestry. Whilst this variant is absent from gnomAD v4 - this ancestral group is underrepresented and an alt change with a higher Grantham score at the same residue (Thr --> Ile) is present in 325 hets.
FDG5 knockout mouse demonstrated embryonic lethality, no haploinsufficiency animal model currently available.Created: 19 Feb 2026, 10:55 a.m. | Last Modified: 19 Feb 2026, 10:55 a.m.
Panel Version: 1.4336
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Congenital heart disease - MONDO:0005453, FGD5-related
Publications
Red List (low evidence)
Appears to be two separate families reported with different nonsense variants in FGD5 associated with TOF. There is some author and recruitment overlap however there is no compelling evidence to state the two probands are related.
32037394 - one family reported with a nonsense variant in an individual with pulmonary stenosis and dysplastic valve, ASD - Glu322* (variant is absent in gnomAD v4.1)
30232381 (missed this publication) - individual reported with TOF, ASD, AF, hypertension, aortic dilation Arg1225* - present in gnomADv4.1 singleton in EAS population.
There is no clear evidence that LoF is the mechanism of disease. No pathogenic variants have been reported in ClinVar at this stage thus the gene should remain as Red till further evidence is provided.
Sources: LiteratureCreated: 26 Nov 2025, 10:02 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
tetralogy of fallot MONDO:0008542
Publications
Phenotypes for gene: FGD5 were changed from tetralogy of fallot MONDO:0008542 to Congenital heart disease - MONDO:0005453, FGD5-related
Publications for gene: FGD5 were set to 32037394; 30232381
Gene: fgd5 has been classified as Amber List (Moderate Evidence).
gene: FGD5 was added gene: FGD5 was added to Fetal anomalies. Sources: Expert Review Red,Literature Mode of inheritance for gene: FGD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: FGD5 were set to 32037394; 30232381 Phenotypes for gene: FGD5 were set to tetralogy of fallot MONDO:0008542
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.