ClinVar Miner

Submissions for variant NM_003265.2(TLR3):c.1660C>T (p.Pro554Ser) (rs121434431)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647016 SCV000768802 uncertain significance Herpes simplex encephalitis 1 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 554 of the TLR3 protein (p.Pro554Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs121434431, ExAC 0.07%). This variant has been reported in several individuals affected with herpes simplex encephalitis (PMID: 17872438, 21911422). However, other family members who also carried this variant and were HSV-1 seropositive were clinically unaffected. ClinVar contains an entry for this variant (Variation ID: 6662). Experimental studies have shown that this missense change demonstrates impaired responses to polyinosinic:polycytidylic acid (poly(I:C)) and tested viruses in some cell types/lines, but exhibits normal responses to poly(I:C) and tested viruses in other cell types/lines (PMID: 17872438, 20855885, 20472559, 19625408). The clinical relevance of these findings is uncertain and to date, no functional studies using central nervous system cells have been reported. 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, Partners HealthCare 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 compou nd heterozygous individuals with herpes simplex encephalitis (HSE), and 1 hetero zygous proband with enteroviral myocarditis (Zhang 2007, Gorbea 2010, Guo 2011). However, it has also been identified in multiple unaffected family members (Zha ng 2007, Guo 2011) and in 0.07% (91/129040) of European chromosomes by gnomAD (h ttp://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 path ogenicity. Furthermore, in vitro functional assays have produced conflicting res ults 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 d efinitively established. In summary, the clinical significance of the p.Pro554Se r variant is uncertain.
OMIM RCV000007044 SCV000027240 risk factor Herpes simplex encephalitis 2 2007-09-14 no assertion criteria provided literature only

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