ClinVar Miner

Submissions for variant NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser)

gnomAD frequency: 0.00053  dbSNP: rs121434431
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000647016 SCV000768802 uncertain significance Herpes simplex encephalitis, susceptibility to, 1 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 554 of the TLR3 protein (p.Pro554Ser). This variant is present in population databases (rs121434431, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with herpes simplex encephalitis, severe influenza pneumonia, and/or recurrent herpes simplex virus 1–triggered erythema multiforme (PMID: 17872438, 21911422, 33174085, 34813006). ClinVar contains an entry for this variant (Variation ID: 6662). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TLR3 function (PMID: 17872438, 19625408, 20472559, 20855885). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000826059 SCV000967553 uncertain significance not specified 2019-02-19 criteria provided, single submitter clinical testing The p.Pro554Ser variant in TLR3 has been reported in 2 heterozygous and 1 compound heterozygous individuals with herpes simplex encephalitis (HSE), and 1 heterozygous proband with enteroviral myocarditis (Zhang 2007, Gorbea 2010, Guo 2011). However, it has also been identified in multiple unaffected family members (Zhang 2007, Guo 2011) and in 0.07% (91/129040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported as a variant of uncertain significance in ClinVar (Variation ID 6662). Computational prediction tools and conservation analysis suggest that the p.Pro554Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, in vitro functional assays have produced conflicting results regarding the impact of this variant on protein function (Zhang 2007, Wang 2009, Gorbea 2010, Qi 2010, Guo 2011). Finally, although TLR3 variants have been reported in association with HSE, this gene-disease relationship has not been definitively established. In summary, the clinical significance of the p.Pro554Ser variant is uncertain.
Fulgent Genetics, Fulgent Genetics RCV002496289 SCV002806182 uncertain significance Susceptibility to HIV infection; Immunodeficiency 83, susceptibility to viral infections 2022-04-11 criteria provided, single submitter clinical testing
OMIM RCV000007044 SCV000027240 risk factor Immunodeficiency 83, susceptibility to viral infections 2007-09-14 no assertion criteria provided literature only

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