NM_199242.3(UNC13D):c.551G>A (p.Trp184Ter) AND Familial hemophagocytic lymphohistiocytosis 3

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 11, 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:: RCV001210685.7

Allele description [Variation Report for NM_199242.3(UNC13D):c.551G>A (p.Trp184Ter)]

NM_199242.3(UNC13D):c.551G>A (p.Trp184Ter)

Gene:

UNC13D:unc-13 homolog D [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_199242.3(UNC13D):c.551G>A (p.Trp184Ter)

HGVS:

NC_000017.11:g.75842451C>T
NG_007266.1:g.7267G>A
NM_199242.3:c.551G>AMANE SELECT
NP_954712.1:p.Trp184Ter
LRG_122t1:c.551G>A
LRG_122:g.7267G>A
NC_000017.10:g.73838532C>T
NM_199242.2:c.551G>A

Protein change:

W184*

Links:

dbSNP: rs754292065

NCBI 1000 Genomes Browser:

rs754292065

Molecular consequence:

NM_199242.3:c.551G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Familial hemophagocytic lymphohistiocytosis 3 (FHL3)
Identifiers:: MONDO: MONDO:0012146; MedGen: C1837174; Orphanet: 540; OMIM: 608898

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001382183	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14622600, 21755595, 24470399, 25573973, 28492532
SCV002588774	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001382183

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 11, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002588774

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 3, 2022)

germline

clinical testing

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

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).

Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, Lambert N, Ouachée-Chardin M, Chedeville G, Tamary H, Minard-Colin V, Vilmer E, Blanche S, Le Deist F, Fischer A, de Saint Basile G.

Cell. 2003 Nov 14;115(4):461-73.

PubMed [citation]

PMID:: 14622600

A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function.

Elstak ED, te Loo M, Tesselaar K, van Kerkhof P, Loeffen J, Grivas D, Hennekam E, Boelens JJ, Hoogerbrugge PM, van der Sluijs P, van Gijn ME, van de Corput L.

Pediatr Blood Cancer. 2012 Apr;58(4):598-605. doi: 10.1002/pbc.23253. Epub 2011 Jul 13.

PubMed [citation]

PMID:: 21755595

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001382183.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Trp184*) in the UNC13D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UNC13D are known to be pathogenic (PMID: 14622600). This variant is present in population databases (rs754292065, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 21755595, 24470399, 25573973). ClinVar contains an entry for this variant (Variation ID: 940988). For these reasons, this variant has been classified as Pathogenic.

#	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

From DASA, SCV002588774.1

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

Description

The c.551G>A;p.Trp184* variant creates a premature translational stop signal in the UNC13D gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (Clinvar ID: 40988) - PS4_supporting. The variant is present at low allele frequencies population databases (rs754292065 – gnomAD 0.0001068%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.

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

Last Updated: May 12, 2024

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