chrX-12920335-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_ModeratePM2
The NM_138636.5(TLR8):c.1295C>T(p.Pro432Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. P432P) has been classified as Likely benign.
Frequency
Consequence
NM_138636.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TLR8 | NM_138636.5 | c.1295C>T | p.Pro432Leu | missense_variant | 2/2 | ENST00000218032.7 | |
TLR8-AS1 | NR_030727.1 | n.241-12002G>A | intron_variant, non_coding_transcript_variant | ||||
TLR8 | NM_016610.4 | c.1349C>T | p.Pro450Leu | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TLR8 | ENST00000218032.7 | c.1295C>T | p.Pro432Leu | missense_variant | 2/2 | 1 | NM_138636.5 | P2 | |
TLR8 | ENST00000311912.5 | c.1349C>T | p.Pro450Leu | missense_variant | 3/3 | 1 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Immunodeficiency 98 with autoinflammation, X-linked Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 04, 2022 | - - |
INFLTR8 Pathogenic:1
Pathogenic, no assertion criteria provided | case-control | Megan Cooper Lab, Washington University School of Medicine in St Louis | - | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.