ClinVar Genomic variation as it relates to human health
NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser)
Variation ID: 6662 Accession: VCV000006662.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q35.1 4: 186083346 (GRCh38) [ NCBI UCSC ] 4: 187004500 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 11, 2018 Oct 8, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003265.3:c.1660C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003256.1:p.Pro554Ser missense NC_000004.12:g.186083346C>T NC_000004.11:g.187004500C>T NG_007278.1:g.19192C>T LRG_117:g.19192C>T LRG_117t1:c.1660C>T LRG_117p1:p.Pro554Ser O15455:p.Pro554Ser - Protein change
- P554S
- Other names
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- Canonical SPDI
- NC_000004.12:186083345:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00041
Exome Aggregation Consortium (ExAC) 0.00045
Trans-Omics for Precision Medicine (TOPMed) 0.00045
The Genome Aggregation Database (gnomAD) 0.00053
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TLR3 | - | - |
GRCh38 GRCh37 |
435 | 570 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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risk factor (1) |
no assertion criteria provided
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Sep 14, 2007 | RCV000007044.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 19, 2019 | RCV000826059.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV000647016.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 11, 2022 | RCV002496289.1 | |
TLR3-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jun 24, 2024 | RCV004755717.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Feb 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967553.2
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Herpes simplex encephalitis, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000768802.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Uncertain significance
(Apr 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Susceptibility to HIV infection
Immunodeficiency 83, susceptibility to viral infections
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806182.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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risk factor
(Sep 14, 2007)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY 83, SUSCEPTIBILITY TO VIRAL INFECTIONS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027240.5
First in ClinVar: Apr 04, 2013 Last updated: Jul 15, 2021 |
Comment on evidence:
In 2 unrelated French children with immunodeficiency-83 manifest as herpes simplex encephalitis (IMD83; 613002), Zhang et al. (2007) identified heterozygosity for a c.1660C-T transition in … (more)
In 2 unrelated French children with immunodeficiency-83 manifest as herpes simplex encephalitis (IMD83; 613002), Zhang et al. (2007) identified heterozygosity for a c.1660C-T transition in the TLR3 gene, resulting in a pro554-to-ser (P554S) substitution. Pro554 is highly conserved in a leucine-rich region of TLR3 in fish and mammals. The mutations occurred on different TLR3 haplotypes in the children, indicating that they represent independent mutational events. Some relatives in each kindred who were heterozygous for the mutation lacked a history of HSE but were HSV-1 seropositive. The mutation was not identified in 1,581 unrelated healthy individuals. Functional expression studies showed that the P554S mutation resulted in loss of interferon production when stimulated, consistent with a loss of function; the mutation also showed a dominant-negative effect. In a 19-year-old man (patient P), born of unrelated Polish parents, with herpes simplex encephalitis at 8 years of age, Guo et al. (2011) identified compound heterozygous missense mutations in the TLR3 gene: a c.1660C-T transition in exon 4, resulting in a pro554-to-ser (P554S) substitution in the ectodomain, and a c.2236G-T transversion in exon 4, resulting in a glu746-to-ter (E746X; 603029.0003) substitution in the linker region, predicted to result in a truncated protein without proper translation of the TIR domain. The E746X mutation was not found in 2,082 control chromosomes. Both mutations were found in the patient's leukocytes and fibroblasts, and the mutations segregated with the disorder in the family. The patient also carried a homozygous TLR3 polymorphism (L412F; 603029.0002). Expression of the mutant alleles into a TLR3-deficient fibrosarcoma cell line showed that the P554S allele encoded a truncated form of TLR3 with a molecular mass of about 80 kD (the wildtype protein has a molecular mass of about 130 kD). The E746X mutant protein showed abnormal glycosylation of the C-terminal end, and some of the protein was mislocated in the cell. Neither P554S nor E746X was able to rescue the deficits in interferon production in response to poly(I:C) when transfected into TLR3-null cells, consistent with a loss of function. Patient fibroblasts showed complete lack of beta- and gamma-interferon production in response to poly(I:C) and lack of interferon production, as well as increased viral replication and cell death, when infected in vitro with HSV-1 and VSV; however, they showed normal interferon response when infected with multiple other viruses. Moreover, patient leukocytes showed normal interferon response to poly(I:C) and when exposed to multiple viruses, including HSV-1 and VSV. The findings suggested that TLR3 is vital for protective immunity to primary HSV-1 infection in the central nervous system, but is largely redundant for systemic host defense, which also explains the lack of disseminated disease in this patient. Lim et al. (2019) identified a heterozygous P554S mutation in 2 unrelated children with IMD83 manifest as severe pneumonitis due to infection with influenza A (IAV). These findings expanded the phenotype associated with TLR3 mutations to include other virus susceptibilities and tissue manifestations. (less)
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Uncertain significance
(Jun 24, 2024)
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no assertion criteria provided
Method: clinical testing
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TLR3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005355061.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TLR3 c.1660C>T variant is predicted to result in the amino acid substitution p.Pro554Ser. This variant has been reported in the heterozygous and compound heterozygous … (more)
The TLR3 c.1660C>T variant is predicted to result in the amino acid substitution p.Pro554Ser. This variant has been reported in the heterozygous and compound heterozygous states in at least three individuals with acute, infection-induced herpes-specific encephalitis (HSE) (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422) and at least four individuals with severe influenza-induced pneumonia (Lim et al. 2019. PubMed ID: 31217193; Bucciol et al. 2022. PubMed ID: 34813006). It has also been reported in an individual with recurrent HSV1–triggered erythema multiforme and no history of HSE (Bucciol et al. 2021. PubMed ID: 33174085), one individual with Coxsackievirus B3 (CVB3)-associated myocarditis (Gorbea et al. 2010. PubMed ID: 20472559), and one individual from a cohort of patients who experienced "life-threatening" COVID-19 (Zhang et al. 2020. PubMed ID: 32972995). In vitro studies are inconclusive or conflicting regarding a possible impact on protein function. One study investigating the antiviral immune response to hepatitis C virus found that the p.Pro554Ser variant generated an immune response comparable to wild type in transformed hepatocytes (Wang et al. 2009. PubMed ID: 19625408). Another study found that p.Pro554Ser was able to generate a normal immune response but had reduced expression at the cell surface indicative of a possible intracellular trafficking defect (Qi et al. 2010. PubMed ID: 20855885). On the other hand, several additional studies have demonstrated a complete loss of function in patient fibroblasts or transformed, TLR3-deficient fibrosarcoma cell lines (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422; Lim et al. 2019. PubMed ID: 31217193; Zhang et al. 2020. PubMed ID: 32972995). This variant is reported in 0.071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Incomplete penetrance has been reported in several studies (Zhang et al. 2007. PubMed ID: 17872438; Guo et al. 2011. PubMed ID: 21911422; reviewed in Mielcarska et al. 2018. PubMed ID: 29305044). Taken together, the clinical significance of the p.Pro554Ser variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pathogenic P554S Variant in TLR3 in a Patient with Severe Influenza Pneumonia. | Bucciol G | Journal of clinical immunology | 2022 | PMID: 34813006 |
Pathogenic TLR3 Variant in a Patient with Recurrent Herpes Simplex Virus 1-Triggered Erythema Multiforme. | Bucciol G | Journal of clinical immunology | 2021 | PMID: 33174085 |
Severe influenza pneumonitis in children with inherited TLR3 deficiency. | Lim HK | The Journal of experimental medicine | 2019 | PMID: 31217193 |
Functional failure of TLR3 and its signaling components contribute to herpes simplex encephalitis. | Mielcarska MB | Journal of neuroimmunology | 2018 | PMID: 29305044 |
Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children. | Studzińska M | PloS one | 2017 | PMID: 28046022 |
TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. | Lim HK | Neurology | 2014 | PMID: 25339207 |
Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. | Guo Y | The Journal of experimental medicine | 2011 | PMID: 21911422 |
Secretion of the human Toll-like receptor 3 ectodomain is affected by single nucleotide polymorphisms and regulated by Unc93b1. | Qi R | The Journal of biological chemistry | 2010 | PMID: 20855885 |
A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy. | Gorbea C | The Journal of biological chemistry | 2010 | PMID: 20472559 |
Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. | Wang N | Journal of virology | 2009 | PMID: 19625408 |
TLR3 deficiency in patients with herpes simplex encephalitis. | Zhang SY | Science (New York, N.Y.) | 2007 | PMID: 17872438 |
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Text-mined citations for rs121434431 ...
HelpRecord last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.