Mendeliome
Gene: EGFR Green List (high evidence)Green List (high evidence)
Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481;
Biallelic - LOF
Green rating
PMID: 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400
Total 27 individuals from 24 families reported with this condition. 23 families (20 Roma descent, 3 unknown ethnicity) had the same homozygous missense variant in EGFR (c.1283 G>A; p.Gly428Asp) strongly supporting a founder effect. 1 Japanese family had compound heterozygous variants (p.R98X and p.I365N). Segregation testing was only performed in a few families.
Condition characterised by intrauterine growth retardation, premature birth, skin issues (thin, translucent, fragile, desquamation, ichthyosis, infective/inflammatory lesions), nephromegaly, renal tubular dysfunction with electrolyte imbalances, chronic diarrhoea, necrotising enterocolitis, recurrent infections with sepsis, cardiac anomalies, and dysmorphism. Most die within 2.5 years.
PMID 24691054: Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling.
PMID 26436111: EGF failed to induce mutated receptor phosphorylation in patient-derived fibroblasts and activation of downstream targets was suppressed. The heterologously expressed extracellular domain was impaired in stability and the binding of EGF.
EGFR knockout mice show some clinical and pathological similarities with patients though features are not present at birth but develop afterwards in the skin, lungs, and digestive organs (PMID 9176390, 7618085, 7630400).
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Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035
Monoallelic - GOF
Amber rating
PMID: 41533385
3 unrelated individuals presenting with widespread acanthosis nigricans, woolly hair, palmoplantar keratoderma and pulmonary nodules (consistent with atypical adenomatous hyperplasia). They all had the same heterozygous variant in EGFR (p.L858R). Two were shown to be de novo, and one was in post‑zygotic mosaic state. Patient‑cell assays show increased EGFR‑signalling supporting a gain of function mechanism. Therapy with an EGFR inhibitor in the 2 patients with germline variants showed marked improvement in skin and lung manifestations.Created: 16 Jul 2026, 12:04 p.m. | Last Modified: 16 Jul 2026, 12:13 p.m.
Panel Version: 2.222
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481; Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035
Publications
Mode of pathogenicity
Other
I don't know
PMID: 33326033 - Akhavanfard et al 2020 - identified a heterozygous germline variant in EGFR (c.3238 G>A, p.Asp1080Asn) in a 21 year old female with metastatic bilateral Adrenocortical carcinoma (ACC). Then they analyzed germline exome data from 21 children, 32 adolescents and young adults (15-39y), and 60 adult participants with ACC. 3.5% of all 113 ACC cases had at least a highly prioritized VUS germline EGFR variant, compared to only 0.3% in a non-TCGA (The Cancer Genome Atlas) ExAC control group (P < 0.0001). In the adolescents and young adults group 6.2% had ECGR variants. No segregation data.Created: 4 Feb 2021, 5:44 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Adrenocortical carcinoma
Publications
Red List (low evidence)
Only 1 patient with inflammatory skin and bowel disease, loss of scalp hair, coarctation of aorta, and bilateral renal enlargement but no obstruction. No functional data.Created: 30 Jan 2020, 6:27 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Inflammatory skin and bowel disease, neonatal, 2; OMIM # 616069
Publications
Phenotypes for gene: EGFR were changed from Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481 to Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481; Wooly hair-palmoplantar keratoderma syndrome, MONDO:0014492; Acanthosis nigricans MONDO:0007035
Publications for gene: EGFR were set to 24691054,36017778,26436111,32250467,32602142,40040597,29899996,9176390,7618085,7630400
Mode of inheritance for gene: EGFR was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: EGFR were changed from Neonatal nephrocutaneous inflammatory syndrome, OMIM #616069 to Inflammatory skin and bowel disease, neonatal 2, MONDO:0014481
Phenotypes for gene: EGFR were changed from Inflammatory skin and bowel disease, neonatal, 2; OMIM # 616069 to Neonatal nephrocutaneous inflammatory syndrome, OMIM #616069
Publications for gene: EGFR were set to 24691054
Gene: egfr has been classified as Green List (High Evidence).
Gene: egfr has been classified as Red List (Low Evidence).
Phenotypes for gene: EGFR were changed from to Inflammatory skin and bowel disease, neonatal, 2; OMIM # 616069
Publications for gene: EGFR were set to
Mode of inheritance for gene: EGFR was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Gene: egfr has been classified as Red List (Low Evidence).
gene: EGFR was added gene: EGFR was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: EGFR was set to Unknown
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.