Request for Information (RFI): Resources or Services to Enable Functional Interpretation of Sequence Variants of Heart, Lung, Blood, and Sleep Disorders

Notice Number: NOT-HL-18-630

Key Dates
Release Date: May 22, 2018

Related Announcements

Issued by
National Heart, Lung, and Blood Institute (NHLBI)


This request for information (RFI) seeks comments regarding the level of need for support mechanisms for functional validation of candidate genes and variants. In particular, the NHLBI is interested in functional validation of variants related to Heart, Lung, Blood and Sleep disorders identified through TOPMed and other -Omics research.


The American College of Medical Genetics and Genomics and the Association of Molecular Pathology have collaborated to develop criteria and guidelines for the interpretation of sequence variants. They recognized functional data as one of several types of evidence that could be used to assess the level of pathogenicity of candidate variants (Richards et al, 2015). However, in a recent commentary, Manolio et al, (2017) identified lack of functional evidence of pathogenicity as a major barrier to the interpretation of genomic variant. They encouraged close collaborations between basic scientists and clinical genomicists to tackle the ever-growing number of variants of uncertain significance (VUS) discovered through genome sequencing. The ClinGen investigators have taken those criteria and devised a framework for semiquantitative measurement of the strength of evidence of gene-disease relationships, including functional evidence and animal and cell culture models (Strande et al, 2017).

A group of NHLBI-supported investigators have recently released a white paper describing the variety of technologies, assays, and model systems that can be exploited to increase throughput and efficiency of functional assays (Musunuru et al, 2018). This RFI solicits information from the research and clinical communities to identify the level of need for resources to be dedicated to fill this gap in functional evidence and the nature of those resources.

Information Requested

The NHLBI invites comments on the following topics to guide design of a potential program to support the collection of functional data.

  1. Barriers that impede classification of the functions of genomic variants relative to suspected roles in heart, lung, blood, or sleep (HLBS) disorder causation or progression.
  2. Level of demand for a potential resource to perform functional assays of candidate genomic variants.
  3. Deliverables such a resource could produce that would provide sufficient level of evidence to assess the clinical validity of a gene-disease relationship.
  4. Range of assays, throughput level, and turnaround time necessary to assess HLBS variants submitted by investigators or clinicians.
  5. Current availability of services at commercial and academic sites that could participate as assay providers.
  6. Criteria to assess requests from investigators and clinicians and prioritize applicants to receive access to assay services through such a resource.

Submitting a Response

Comments in response to this notice may be submitted by email no later than June 18, 2018 to: Please mark your responses with the RFI identifier ?NOT-HL-18-630 in the subject line of the email. Responses are expected to be less than 1,000 words.

Respondents will receive an automated email confirmation acknowledging receipt of their response, but will not receive individualized feedback.


Responses to this RFI are voluntary and may be anonymous. Any identifiers (e.g., names, institutions, e-mail addresses, etc.) will be removed when responses are compiled. Only the processed, anonymized results will be shared internally with scientific working groups convened by the NIH, as appropriate. Proprietary, classified, confidential, or sensitive information should not be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).

This RFI is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government, or the National Institutes of Health (NIH). The NIH does not intend to award a grant or contract to pay for the preparation of any information submitted or for the NIH’s use of such information. Respondents will not be notified of the NIH evaluation of the information received. No basis for claims against the NIH shall arise as a result of a response to this request for information or the NIH’s use of such information as either part of our evaluation process or in developing specifications for any subsequent announcement. Responses will be held confidential. Proprietary information should not be sent.


Please direct all inquiries to:

Charlene Schramm, Ph.D.
National Heart, Lung, and Blood Institute ( NHLBI )
Telephone: 301-402-3793