NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 19, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000826059.4

Allele description [Variation Report for NM_003265.3(TLR3):c.1660C>T (p.Pro554Ser)]

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

Gene:

TLR3:toll like receptor 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q35.1

Genomic location:

Preferred name:

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

HGVS:

NC_000004.12:g.186083346C>T
NG_007278.1:g.19192C>T
NM_003265.3:c.1660C>TMANE SELECT
NP_003256.1:p.Pro554Ser
NP_003256.1:p.Pro554Ser
LRG_117t1:c.1660C>T
LRG_117:g.19192C>T
LRG_117p1:p.Pro554Ser
NC_000004.11:g.187004500C>T
NM_003265.2:c.1660C>T
O15455:p.Pro554Ser

Protein change:

P554S; PRO554SER

Links:

UniProtKB: O15455#VAR_054887; OMIM: 603029.0001; dbSNP: rs121434431

NCBI 1000 Genomes Browser:

rs121434431

Molecular consequence:

NM_003265.3:c.1660C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000967553	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Feb 19, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17872438, 20472559, 20855885, 21911422, 25339207, 29305044, 28046022, 19625408, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967553

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Feb 19, 2019)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

TLR3 deficiency in patients with herpes simplex encephalitis.

Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, et al.

Science. 2007 Sep 14;317(5844):1522-7.

PubMed [citation]

PMID:: 17872438

A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy.

Gorbea C, Makar KA, Pauschinger M, Pratt G, Bersola JL, Varela J, David RM, Banks L, Huang CH, Li H, Schultheiss HP, Towbin JA, Vallejo JG, Bowles NE.

J Biol Chem. 2010 Jul 23;285(30):23208-23. doi: 10.1074/jbc.M109.047464. Epub 2010 May 14.

PubMed [citation]

PMID:: 20472559
PMCID:: PMC2906314

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967553.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	1	not provided

Last Updated: Oct 8, 2024

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