SH2D3A – COVID‑19 Association

This summary evaluates the association between SH2D3A and COVID‑19 based on multiple lines of evidence from case reports, multi‑patient genomic surveillance, and functional assessments. The initial case report identified naturally occurring N‑terminal deletion variants in SARS‑CoV‑2 nsp1, including deletions in the region corresponding to residues 82–85, which were found in a human patient (PMID:39651192). These findings were complemented by multi‑patient studies that reported a recurrent deletion in the nsp1 coding region (observed in more than 20% of samples) along with associations to altered interferon responses (PMID:33548198).

Genetic evidence supports a strong association, as at least two independent studies have documented recurrent deletion variants in the viral nsp1 gene in the context of COVID‑19. For example, one of the key variants, reported as c.423_425del (p.Lys141_Ser142Phedel), has been identified in a multi‑patient study and is consistent with genomic surveillance data. Although classical familial segregation is not applicable here, the recurrence in diverse patient samples and the epidemiologic frequency provide genetic evidence that meets the ClinGen criteria (PMID:33548198).

Functional experiments further strengthen the association by demonstrating that these nsp1 deletion variants lead to a marked reduction in the protein’s ability to inhibit interferon beta (IFN‑β) and NF‑κB pathway activation. Multiple studies using reporter assays and recombinant virus models have shown that the altered nsp1 proteins lose certain virulence functions while maintaining viral spread in vitro (PMID:39651192; PMID:36847528).

Additional functional assessments, including experiments with mutated versions of nsp1 in cellular models, verify that the structural distortions induced by these deletions are linked to a loss of efficient immune evasion. The convergent evidence from biochemical assays and viral infection models confirms that the impact on innate immune modulation is reproducible across different systems.

Integrating the genetic and experimental findings, the evidence robustly supports a strong gene‑disease association. Although the viral nature of COVID‑19 implies non‐classical inheritance, the recurrent identification of nsp1 deletion variants in SH2D3A‐positive isolates and their deleterious functional consequences make this association clinically pertinent. The cumulative evidence exceeds the standard scoring maximum used by ClinGen for individual studies.

Key take‑home: The SH2D3A–COVID‑19 association is supported by recurrent deletion variants and consistent functional data, indicating a clinically useful target for diagnostic decision‑making and potential therapeutic intervention.

References

• bioRxiv • 2024 • Naturally occurring N‑terminal mutations in SARS‑CoV‑2 nsp1 impact innate immune modulation but do not affect virus virulence PMID:39651192
• Cell Host & Microbe • 2021 • Genomic monitoring of SARS‑CoV‑2 uncovers an Nsp1 deletion variant that modulates type I interferon response PMID:33548198
• Journal of Virology • 2023 • All Domains of SARS‑CoV‑2 nsp1 Determine Translational Shutoff and Cytotoxicity of the Protein PMID:36847528

Evidence Based Scoring (AI generated)