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NM_006949.4(STXBP2):c.1452+1G>A AND Familial hemophagocytic lymphohistiocytosis 5

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Aug 8, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV003041346.3

Allele description [Variation Report for NM_006949.4(STXBP2):c.1452+1G>A]

NM_006949.4(STXBP2):c.1452+1G>A

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.1452+1G>A
HGVS:
  • NC_000019.10:g.7646345G>A
  • NG_016709.1:g.14241G>A
  • NM_001127396.3:c.1443+1G>A
  • NM_001272034.2:c.1485+1G>A
  • NM_001414484.1:c.1356+1G>A
  • NM_006949.4:c.1452+1G>AMANE SELECT
  • LRG_165:g.14241G>A
  • NC_000019.9:g.7711231G>A
Molecular consequence:
  • NM_001127396.3:c.1443+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001272034.2:c.1485+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001414484.1:c.1356+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_006949.4:c.1452+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV003442701Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Aug 8, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004205646Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(May 26, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical exome sequencing: results from 2819 samples reflecting 1000 families.

Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Köster J, Marais A, Paknia O, Schröder R, Garcia-Aznar JM, Werber M, Brandau O, Calvo Del Castillo M, Baldi C, Wessel K, Kishore S, Nahavandi N, Eyaid W, Al Rifai MT, Al-Rumayyan A, Al-Twaijri W, Alothaim A, Alhashem A, et al.

Eur J Hum Genet. 2017 Feb;25(2):176-182. doi: 10.1038/ejhg.2016.146. Epub 2016 Nov 16.

PubMed [citation]
PMID:
27848944
PMCID:
PMC5255946

Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alowain M, Alzaidan H, Alsayed M, Subhani S, Cupler E, Faden M, Alhashem A, Qari A, Chedrawi A, Aldhalaan H, Kurdi W, Khan S, Rahbeeni Z, Alotaibi M, Goljan E, Elbardisy H, et al.

Am J Hum Genet. 2019 Jun 6;104(6):1182-1201. doi: 10.1016/j.ajhg.2019.04.011. Epub 2019 May 23. Erratum in: Am J Hum Genet. 2019 Oct 3;105(4):879. doi: 10.1016/j.ajhg.2019.09.019.

PubMed [citation]
PMID:
31130284
PMCID:
PMC6562004
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV003442701.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 2138203). This variant is also known as c.1485+1G>A, c.1443+1G>A. Disruption of this splice site has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 27848944, 31130284, 32542393). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 16 of the STXBP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in STXBP2 are known to be pathogenic (PMID: 19804848, 22451424).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004205646.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024