The first patient case reports indicating a relationship of the RASGRP1 gene with immunodeficiency 64 was done by Selzer et al in 2016 (PMID: 8379998). Immunodeficiency 64 is characterized by recurrent bacterial, viral and fungal infections in childhood. Laboratory investigation of patients with immunodeficiency 64 shows decreased numbers of T cells, with less striking decreases in B and NK cells. There has been a documented relationship with immunodeficiency 64 with EBV-associated lymphoma and autoimmunity (Selzer et al, PMID: 8379998 ; Mao et al, PMID 29155103 ; Winter et al, PMID 29282224).
Numerous RASGRP1 variants have been reported in ClinVar. Evidence supporting the gene-disease relationship with RASGRP1 includes case-level data, as well as experimental evidence with functional data, data on functional alterations, non-human model organisms and rescue in patient cells. This gene-disease relationship has been studied in patients for almost 10 years with studies of RASGRP1’s molecular function done in the decades prior (mouse model knockouts first made in 2000). Since that time, there has been a wealth of experimental and clinical data to support the maximum score for genetic evidence (12 points) and experimental evidence (6 points). Note, this curation effort may not be exhaustive of all literature related to this gene-disease relationship, as evidence compilation was stopped once maximum scoring was reached.
The mechanism for the gene-disease relationship is a protein loss of function, as RASGRP1 is RAS pathway activator, functioning as a DAG-regulated nucleotide exchange factor that preferentially regulates the MAPK pathway. It has been heavily studied in T cell development, survival and proliferation, as well as in activation of the B cell receptor and in NK cell activation (reviewed in Hsu et al, 2023 PMID 36675167).
In summary, RASGRP1 is DEFINITIVELY associated with immunodeficiency 64. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on June 7, 2024.
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