NM_006949.4(STXBP2):c.386C>T (p.Thr129Met) AND Familial hemophagocytic lymphohistiocytosis 5

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 17, 2023
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:: RCV003644838.1

Allele description

NM_006949.4(STXBP2):c.386C>T (p.Thr129Met)

Gene:

STXBP2:syntaxin binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_006949.4(STXBP2):c.386C>T (p.Thr129Met)

HGVS:

NC_000019.10:g.7640960C>T
NG_016709.1:g.8856C>T
NM_001127396.3:c.377C>T
NM_001272034.2:c.419C>T
NM_001414484.1:c.290C>T
NM_006949.4:c.386C>TMANE SELECT
NP_001120868.1:p.Thr126Met
NP_001258963.1:p.Thr140Met
NP_001401413.1:p.Thr97Met
NP_008880.2:p.Thr129Met
NP_008880.2:p.Thr129Met
LRG_165t1:c.386C>T
LRG_165:g.8856C>T
LRG_165p1:p.Thr129Met
NC_000019.9:g.7705846C>T
NM_006949.2:c.386C>T
NR_073560.2:n.426C>T

Protein change:

T126M

Molecular consequence:

NM_001127396.3:c.377C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001272034.2:c.419C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001414484.1:c.290C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006949.4:c.386C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_073560.2:n.426C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Familial hemophagocytic lymphohistiocytosis 5
Identifiers:: MONDO: MONDO:0013135; MedGen: C2751293; Orphanet: 540; OMIM: 613101

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004539092	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29665027, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004539092

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 17, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP.

Chen X, Wang F, Zhang Y, Teng W, Wang M, Nie D, Zhou X, Wang D, Zhao H, Zhu P, Liu H.

Clin Genet. 2018 Aug;94(2):200-212. doi: 10.1111/cge.13363. Epub 2018 May 11.

PubMed [citation]

PMID:: 29665027

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004539092.1

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 129 of the STXBP2 protein (p.Thr129Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 29665027). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STXBP2 protein function with a positive predictive value of 80%. 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.

#	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		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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