NM_001083116.3(PRF1):c.1628dup (p.Glu545fs) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 1, 2022
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:: RCV001320363.3

Allele description [Variation Report for NM_001083116.3(PRF1):c.1628dup (p.Glu545fs)]

NM_001083116.3(PRF1):c.1628dup (p.Glu545fs)

Gene:

PRF1:perforin 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

10q22.1

Genomic location:

Preferred name:

NM_001083116.3(PRF1):c.1628dup (p.Glu545fs)

HGVS:

NC_000010.11:g.70598093dup
NG_009615.1:g.9683dup
NM_001083116.3:c.1628dupMANE SELECT
NM_005041.6:c.1628dup
NP_001076585.1:p.Glu545fs
NP_005032.2:p.Glu545fs
LRG_94t1:c.1628dup
LRG_94:g.9683dup
NC_000010.10:g.72357848_72357849insA
NC_000010.10:g.72357849dup
NM_001083116.1:c.1628dupT

Protein change:

E545fs

Links:

dbSNP: rs1564723449

NCBI 1000 Genomes Browser:

rs1564723449

Molecular consequence:

NM_001083116.3:c.1628dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005041.6:c.1628dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001511145	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 14757862, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001511145

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 1, 2022)

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

Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis.

Molleran Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, Filipovich AH.

J Med Genet. 2004 Feb;41(2):137-44. No abstract available.

PubMed [citation]

PMID:: 14757862
PMCID:: PMC1735659

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001511145.2

#	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 results in a frameshift in the PRF1 gene (p.Glu545Glyfs*41). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the PRF1 protein and extend the protein by 29 additional amino acid residues. This variant is present in population databases (no rsID available, gnomAD 0.01%). This frameshift has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 14757862). ClinVar contains an entry for this variant (Variation ID: 1020734). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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: Sep 29, 2024

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