Helping Evaluate And Reclassify Variants of Unknown Significance (HEAR VUS)

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What is the HEAR VUS program?

Comprehensive genetic testing is fast and accurate but understanding the impact of Variants of Uncertain Significance (VUS) is not always straight forward.  The HEAR VUS program offers follow up testing at no additional cost for family members of a patient previously tested with OtoSCOPE.

Goals of the HEAR VUS program

  • To provide the most clinically relevant information about variants identified in families
  • To improve knowledge about genetic variants for the medical and scientific communities
  • To evaluate the pathogenicity of a variant when its contribution is uncertain and cannot be determined as pathogenic or benign

What does the HEAR VUS program do?

  • The HEAR VUS program incorporates evaluation of a VUS in the context of a patient’s and family’s clinical information by testing of additional family members and reviewing the most up-to-date information available for the VUS under consideration. 
  • The VUS is evaluated by the MORL Hearing Team, which includes physicians, genetic counselors, bioinformaticians, graduate students, post-doctoral fellows, medical students, medical residents, and scientists.
  • The VUS is discussed in the context of available clinical information and expert contextual interpretation of the variant is provided.

How do you know if you can participate in the HEAR VUS program?

  • Complimentary testing through the HEAR VUS program is offered through by the MORL in the body of the OtoSCOPE report (OtoSCOPE testing performed after January 2, 2020)
  • Complimentary testing through the HEAR VUS program can also be requested.  If complimentary testing is being requested, healthcare providers must submit a request to the MORL with relevant clinical information, family history and audiometric information (for patients screened by MORL after January 2, 2020).
  • Samples are then sent to MORL for testing using the HEAR VUS program option on the Hearing testing requisition form.
  • Testing is performed and a report is returned to the ordering healthcare provider. 
    • If the VUS is reclassified based on familial testing, MORL will issue an amended report for the proband as well as reports for all family members tested through the HEAR VUS.
    • Please note: a change in classification is not guaranteed.

Exclusions to the HEAR VUS program

  • Complimentary testing will not be offered to family members if:
    • The variant has been classified previously as pathogenic, likely pathogenic, likely benign or benign.
    • The VUS is in a gene that is not consistent with the patient’s reported clinical history (for example: age of onset, degree of hearing loss, reported family history).
    • The variant is associated with an inheritance pattern such that further familial testing will not clarify the significance of the variant.
    • The VUS is associated with autosomal recessive hearing loss and a second variant is not present in that gene
    • The VUS has a minor allele frequency greater than expected to cause hearing loss
    • The relevant clinical information is not made available.  In this situation, Fee-for-Service Familial Testing may be ordered.
    • Please note, incidental and secondary findings are not evaluated through this program.

Variant Interpretation

  • Variant interpretation is complex and relies on all available clinical, phenotypic and genetic information.
  • There is no single method, tool, or filter that reliably determines pathogenicity and so expert analysis is required.
  • Variants are discussed at the MORL multidisciplinary hearing meeting (Hearing Group) to integrate clinical information with results from OtoSCOPE and the HEAR VUS program to determine the most likely genetic cause of deafness, if any.
  • The MORL Hearing Team includes physicians, genetic counselors, bioinformaticians, graduate students, post-doctoral fellows, medical students, medical residents, and scientists who discuss each variant in the context of available clinical information to provide expert contextual interpretation of genetic variants.
  • Exclusion of variants as causative is a complex process that integrates all available information.
  • ACMG guidelines are utilized in the interpretation of variants.
  • Possible justifications for exclusion of a variant may include, but are not limited to the following reasons:
    • Causality of the identified variant is not consistent with the reported family history;
    • Causality of the identified variant is not consistent with the clinical description and/or phenotypic information provided to MORL;
    • Causality of the identified variant is unlikely based on pathogenicity prediction score;
    • Allele frequency is too high.

Do you have questions about the HEAR VUS Program? Contact MORL Hearing Team at MORL@uiowa.edu and add “HEAR VUS” in the email subject line.