Mendeliome
Gene: ERBB2 Amber List (moderate evidence)I don't know
ERBB2 encodes HER2 an epidermal growth factor receptor. Gain of function of this gene (amplification/SNV/in frame dup) is known to have a significant role in cancer.
PMID 42060361 reports five families, 9 individuals with heterozygous ERBB2 missense variants presenting with poor growth/short stature, cleft lip/palate, and variable mild craniofacial malformations.
3 variants were de novo and 2 were inherited from affected family members.
A loss of function mechanism is proposed.
ERBB2 is not under loss of function constraint in gnomAD v4 (pLI 0.25). All but one variant reported in affected individuals were present in gnomAD v4 with 4-34 heterozygotes present.
Extensive supportive functional studies were performed including xenopus embryo knock in with rescue upon introduction of wild type, mouse knock in and HEK293 cell studies noting loss of downstream signalling.Created: 12 May 2026, 12:18 p.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Syndromic disease, MONDO:0002254, ERBB2-related
Publications
Red List (low evidence)
Main paper for cases described in PMID 33720042.
2 siblings from consanguineous Turkish family with intestinal dysmotility, severe constipation (aganglionosis in submucosa at rectum), peripheral axonal neuropathy, hypotonia, mild developmental delay, unilateral ptosis, sensorineural hearing loss, and clubfeet. They had a homozygous rare missense variant in ERBB2 gene (A710V) and parents were heterozygous carriers. Western blot analysis revealed a drastic decrease of both ERBB2 and ERBB3 phosphorylation. Other papers showed mice knockout of Erbb2 results in the absence or severe depletion of various neural crest–derived cells.Created: 7 May 2026, 4:36 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Visceral neuropathy, familial, 2, autosomal recessive, MIM # 619465, Complex neurocristinopathy
Publications
I don't know
A missense single-nucleotide variant in ERBB2 (chr17:39717377 C>T, NM_004448.4:c.1795C>T, p. Arg599Cys (GRCh38), rs369903296) was identified in 3 unrelated Finnish probands with left ventricular outflow tract obstruction defects.
- all 3 probands were familial cases with multiple affected family members
- all 3 probands had severe phenotypes (diagnosed either prenatally or in the first days of life)
- Proband of family 1: hypoplastic left heart syndrome (HLHS; including BAV, hypoplastic aortic arch, coarctation of the aorta, ASD, left superior vena cava)
- Proband of family 2: Shone's complex and VSD including aortic valve stenosis, mitral stenosis, coarctation of the aorta
- Proband of family 3: HLHS (including mitral valve stenosis, BAV, aortic valve stenosis, muscular VSD)
The variant segregated in affected family members of each proband who had other less severe congenital heart disease
- Family 1 grandfather - coarctation of the aorta
- Family 2 mother - coarctation of the aorta, BAV
- Family 3 mother - coarctation of the aorta, BAV
- Family 1 father - BAV
- Family 2 maternal grandfather - asymmetric aortic valve
The variant also segregated in two unaffected family members in family 2, suggesting reduced penetrance.
The variant is present in gnomAD with a total allele frequency of 0.00009372 in Finnish Europeans and 0.000004340 across all populations.
Supportive functional assays and a Zebrafish model was conducted.Created: 4 Jun 2025, 1:41 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453
Publications
Red List (low evidence)
A homozygous missense variant (c.2129C>T, p.(Ala710Val)) within ERBB2 (NM_004448.3). Sanger sequencing confirmed that the 2 affected children are homozygous while the healthy parents are heterozygous for the ERBB2 variant.Created: 12 Apr 2021, 4:06 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hirschsprung disease (HSCR, aganglionic megacolon, MIM#142623)
Publications
Red List (low evidence)
Cannot find evidence of a Mendelian gene-disease association.Created: 24 May 2020, 8:38 p.m.
Phenotypes for gene: ERBB2 were changed from Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465; Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453 to Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453; Hirschsprung disease (HSCR, aganglionic megacolon, MIM#142623)
Mode of inheritance for gene: ERBB2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ERBB2 were set to
Phenotypes for gene: ERBB2 were changed from Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465 to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465; Congenital heart disease - left ventricular outflow tract obstruction defects; MONDO:0005453
Mode of inheritance for gene: ERBB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: erbb2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: ERBB2 were changed from to Visceral neuropathy, familial, 2, autosomal recessive, MIM# 619465
Gene: erbb2 has been classified as Red List (Low Evidence).
Gene: erbb2 has been classified as Red List (Low Evidence).
Gene: erbb2 has been classified as Red List (Low Evidence).
Gene: erbb2 has been classified as Red List (Low Evidence).
gene: ERBB2 was added gene: ERBB2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ERBB2 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.