Who can apply?

Australian clinicians, diagnostic labs, and research teams (including research diagnostic groups) who wish to investigate the effect of variants of uncertain significance (VUS) or genes of uncertain significance (GUS) in patients with genetic disorders.


Assessing the impact of variants in known or novel disease genes

Investigation of genes and variants where functional data is necessary to support disease-causation, genotype-phenotype relationship and/or variant pathogenicity include:

1. Novel gene
A potential pathogenic variant identified in a gene not previously associated with disease in a single patient/family/isolated population.

2. Variant of uncertain significance in a known disease gene
A variant with characteristics of being an independent disease-causing mutation and also a strong indication of causality, but insufficient or conflicting evidence exists. For example, it may be classified as a level 3 VUS on a diagnostic or research report.

Please note: variants associated with autosomal recessive disorders should only be submitted where a second variant has been identified.

3. Phenotype expansion of a known disease gene
A variant in a known disease gene causing a clinical phenotype that appears to be different to previously reported genotype-phenotype reports. For example, through a different pathophysiological mechanism such as gain versus loss of function.


Investigation of multiple VUS in a single known disease gene

For many known and novel disease genes there are often significant numbers of potentially disease-causing variants which do not reach the current threshold for definitive genetic diagnosis. Submissions to this stream should have a strong clinical need and rationale to justify bulk analysis of variants. Projects in this Stream may include systems amenable to the parallel assessment of causality in multiple variants.

Before applying

  • Discuss your application with a clinical and/or laboratory genetics team.
  • If analysis of genetic data was performed more than two years ago, we highly recommend reanalysis against the latest gene-lists in PanelApp Australia. Re-analysis may be sufficient to resolve the diagnosis.
  • Patient details should be entered into clinical-facing databases, with appropriate patient consent, such as DECIPHER or other databases within the MatchMaker Exchange network.
  • Ensure appropriate patient consent is obtained. See consent process below.

What you will need

  • Patient details
  • Phenotype (HPO terms)
  • Variant information
  • Copy of genomic test report(s) performed in a NATA-accredited lab (or equivalent)
  • Evidence for variant pathogenicity / gene-disease association

Network activities are considered an extension of standard clinical investigations to obtain a diagnosis for a patient (HREC ID 78873). Therefore, the Network will not seek formal consent from patients to submit a connection application to the Network. Applicants may cite pre-existing consent that permits sharing genomic and health data for the purpose of future research or, alternatively, seek verbal consent from the individual. To submit a connection application to the AFGN, applicants will be asked to verify that they have appropriate consent. Please use our participant information sheet to facilitate discussions with your patients.

Connection process

Application prioritisation

Our Clinical Review Committee (CRC) is a team of clinical geneticists and genetic pathology experts from around Australia who will review the submitted clinical and genetic evidence. The CRC will primarily consider the likelihood that a given variant causes the patient phenotype and the likelihood that subsequent variant modelling would provide diagnostic certainty.

Applications will be prioritised against the following criteria:

  1. Quality of the genetic data as disease-causing
  2. Disease severity, progression, and medical need
  3. Potential therapeutic tractability / therapeutic need to lack of existing therapies
  4. The novelty of the implicated biological pathway
  5. Genetic counselling impact

The CRC may reject applications where variants are unlikely to be the cause of disease or where functional studies are not likely to change classification.

Research matching

If your connection application is approved by the CRC and a match is found, a de-identified excerpt of your application will be made available to candidate research teams to help them develop a project proposal. Your contact details will be shared with the research teams so that you may connect to develop the project proposal. Project proposals will then be considered by our Scientific Review Committee for catalyst funding. Once a suitable proposal has been identified and approved for funding, you will be sent a letter notifying you of your successful connection. It will include a copy of the project proposal and contact details for the research group.

Outcomes and results

At the conclusion of the project, your matched research team will provide you with a report of the research findings for you to interpret and discuss with your patient at your discretion.


Frequently asked questions

What will happen to the information I share?

Your application will be reviewed by our Clinical and Scientific Review Committees. All information shared will be de-identified and treated with confidentiality.

If a match is found an excerpt of your application will be shared to the research group within the Network to develop a project proposal as follows:

Where consent to use of the patient’s data in future research has been provided and is compatible with AFGN activities, this excerpt will contain the following information:

  • Genomic variant datasets
  • Human Phenotype Ontology (HPO) terms
  • Current gene-disease association
  • Gene structure/function
  • Evidence of pathogenicity

In all other instances, the excerpt will contain only:

  • Human Phenotype Ontology (HPO) terms
  • Candidate gene name

Why do you request identifiable patient information?

Patient identifying information will be collected to ensure best chance for research results to be returned to your patient if they are no longer in your care. This information will only be accessible to the project management team. We ask that all other patient information included in your connection application be de-identified.

What is the expected turnaround time?

Generally, you can expect an update on the outcome of clinical review within 4 weeks of submission. In a further 4 weeks you will be notified of the outcome of scientific review.

However, it is important to be aware that studies may take years to produce significant results and may remain uninformative.

What happens if you can’t find a match?

Not all applications will have a suitable match. However, as the Network grows your application may be matched in the future. We will store your application in our secure database for a minimum of five years.

Unmatched genes will be added to our list and circulated quarterly to our Network members for expressions of interest.

What constitutes a declined application?

The most usual reason for the Clinical Review Committee to decline an application is the lack of adequate genetic data to support causality. Applications will also be declined if it is deemed that the proposing study is on a relatively common variant in the population. If a variant phenotype in a known gene is proposed, an appropriate justification that this is a distinct phenotype is likely to be underpinned by a different pathogenic mechanism (e.g. gain-of-function versus previously known hypomorphic mutations) may be provided.

Under what circumstances might an application be put "on hold"?

A key objective of the Network is to expedite collaborations on model-based studies of rare disease genes. Although applications from clinical teams are encouraged, we recognise that there could be situations where there is insufficient detailed analysis of genetic data. Such applications will be put “on hold” whereupon additional input from molecular geneticist studies can help build the case for further consideration. This may include up to date re-analysis by the diagnostic laboratory or additional diagnostic testing/pipelines.

What happens when different clinical groups propose the same gene?

The review committee will call the different groups to consider a multi-team collaboration. Applicants may recognize that a collaborative project is more likely to lead to significant research output, given the fierce competition for publishing research findings in journals of high repute.

I already have a collaborator in mind, can I still apply?

The AFGN was formed to help facilitate collaborations where connections are otherwise difficult to find. However, we do accept submissions from pre-existing connections. In order for us to invite the research team to submit a project proposal for assessment, they will need to be a member of the researcher registry. Our SRC also reserves the right to suggest an alternative candidate who may be better suited to the project. In addition, if another research group also has this gene listed as a tier 1 gene, we may encourage you to form a wider collaboration.

Can I withdraw my application?

If your application has not yet been matched to a research team, you can withdraw your application at any time. Once an application has been matched, you and your research team will be sent a letter of success. At this point you must notify the Project team within 48 hours if you wish to withdraw your application. After this period, funding to commence the project will have been distributed. If you wish to withdraw your application, please email the project team at functional.genomics@mcri.edu.au.