Submissions for variant NM_138636.5(TLR8):c.1295C>T (p.Pro432Leu)

dbSNP: rs2147258995

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873708	SCV002315484	uncertain significance	not provided	2021-04-22	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects TLR8 protein function (PMID: 33512449). This variant has been observed in an apparently mosaic state in individual(s) with immunodeficiency and bone marrow failure (PMID: 33512449). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 432 of the TLR8 protein (p.Pro432Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine.
Megan Cooper Lab, Washington University School of Medicine in St Louis	RCV001526670	SCV001652777	pathogenic	INFLTR8		no assertion criteria provided	case-control	We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
OMIM	RCV002246409	SCV002520448	pathogenic	Immunodeficiency 98 with autoinflammation, X-linked	2022-05-04	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004758808	SCV005363911	uncertain significance	TLR8-related condition	2024-04-22	no assertion criteria provided	clinical testing	The TLR8 c.1349C>T variant is predicted to result in the amino acid substitution p.Pro450Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.