NM_001083116.3(PRF1):c.1283G>A (p.Trp428Ter) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2024
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:: RCV003516318.2

Allele description [Variation Report for NM_001083116.3(PRF1):c.1283G>A (p.Trp428Ter)]

NM_001083116.3(PRF1):c.1283G>A (p.Trp428Ter)

Gene:

PRF1:perforin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_001083116.3(PRF1):c.1283G>A (p.Trp428Ter)

HGVS:

NC_000010.11:g.70598438C>T
NG_009615.1:g.9338G>A
NM_001083116.3:c.1283G>AMANE SELECT
NM_005041.6:c.1283G>A
NP_001076585.1:p.Trp428Ter
NP_001076585.1:p.Trp428Ter
NP_005032.2:p.Trp428Ter
LRG_94t1:c.1283G>A
LRG_94:g.9338G>A
LRG_94p1:p.Trp428Ter
NC_000010.10:g.72358194C>T
NM_001083116.1:c.1283G>A

Protein change:

W428*

Molecular consequence:

NM_001083116.3:c.1283G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_005041.6:c.1283G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial hemophagocytic lymphohistiocytosis 2 (FHL2)
Identifiers:: MONDO: MONDO:0011337; MedGen: C1863727; Orphanet: 540; OMIM: 603553

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004294729	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 17873118, 19484379, 15632205, 17266056, 19487666, 21881043, 25233452, 26903364, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294729

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations.

Trizzino A, zur Stadt U, Ueda I, Risma K, Janka G, Ishii E, Beutel K, Sumegi J, Cannella S, Pende D, Mian A, Henter JI, Griffiths G, Santoro A, Filipovich A, Aricò M; Histiocyte Society HLH Study group..

J Med Genet. 2008 Jan;45(1):15-21. Epub 2007 Sep 14.

PubMed [citation]

PMID:: 17873118

Single gene disorders.

[No authors listed]

Genomic Med. 2008 Dec;2(3-4):241-52. doi: 10.1007/s11568-009-9118-1. No abstract available.

PubMed [citation]

PMID:: 19484379
PMCID:: PMC2694903

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294729.1

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

Description

This sequence change creates a premature translational stop signal (p.Trp428*) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 128 amino acid(s) of the PRF1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 17873118, 19484379). This variant is also known as R428X. This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Thr450Met) have been determined to be pathogenic (PMID: 15632205, 17266056, 19487666, 21881043, 25233452, 26903364). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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