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Functional Assessment of Variants in Organisms of Research (FAVOR) - Profiling Canonical Human Genes and their Variants through Disease Model Phenotyping.

Award Number: R43HG010852
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Functional Assessment of Variants in Organisms of Research (FAVOR) - Profiling Canonical Human Genes and their Variants through Disease Model Phenotyping. - Project Summary / Abstract Genome wide DNA sequencing is now being adopted in clinical practice and an increasing number of variants are identified in epilepsy-associated genes, yet the clinical interpretation of the new variants is challenging. Some of the variants are known to be either pathological or benign, yet a majority of the gene variations remain unknown for their functional consequence. A large number of Variant of Uncertain Significance (VUS) are becoming commonplace in genes for human diseases, providing a significant barrier in making diagnoses and implementing therapies. Bioinformatic approaches can provide some insight into pathogenic probability of VUS alleles, but functional studies in animal model systems are often needed to make definitive of pathogenicity assignments. The expense and long timelines of mouse model production make the use of alternative small animal models attractive. In this proposal, the C. elegansnematode is used as an alternative model capable of fast high-throughput production and screening. Human genes are installed as gene-swap replacements of the native disease-gene homologs. In preliminary work, gene-swap humanization of STXBP1 in the unc-18locus rescued severe locomotion and behavior defects present in the gene knock-out animals. Pathogenic variants into the STXBP1gene-swap loci leads to significant disruption of activity. In this proposal, significant and novel improvements are made to our existing pipeline for the functional analysis of variants in vivo. In Aim 1, the relevance and extensibility of the C. elegans model system for studying human disease is improved through simultaneous humanization of multiple related loci. In Aim 2, new methods are developed for molecular phenotyping, improving the resolution of inputs pathogenicity determination algorithms, and yielding mechanism-of-action level readouts to variant manipulations. In Aim 3, the improvements to the pipeline are tested to quantify gains in pathogenicity determination on a test set of variants.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2020	NEMAMETRIX, INC.	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	000	1	12/12/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	001	1	4/6/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	000	1	4/6/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $124,932 )
2021	2021	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	002	1	3/25/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	000	1	12/9/2020	SUPPLEMENT FOR EXPANSION	$124,932
2021	2020	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	001	1	3/25/2021	NEW	$0
														Subtotal = $124,932

Issue Date FY: 2020 ( Subtotal = $350,000 )
2020	2020	NEMAMETRIX, INC	1505 WESTEC DR	EUGENE	OR	97402	LANE	USA	Human Genome Research	000	1	4/23/2020	NEW	$350,000
														Subtotal = $350,000

Grand Total All Awards = $474,932

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Functional Assessment of Variants in Organisms of Research (FAVOR) - Profiling Canonical Human Genes and their Variants through Disease Model Phenotyping.

Award Number: R43HG010852

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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