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NM_001083116.3(PRF1):c.666C>A (p.His222Gln) AND Familial hemophagocytic lymphohistiocytosis

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 15, 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:
RCV001844108.1

Allele description [Variation Report for NM_001083116.3(PRF1):c.666C>A (p.His222Gln)]

NM_001083116.3(PRF1):c.666C>A (p.His222Gln)

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.666C>A (p.His222Gln)
HGVS:
  • NC_000010.11:g.70599055G>T
  • NG_009615.1:g.8721C>A
  • NM_001083116.3:c.666C>AMANE SELECT
  • NM_005041.6:c.666C>A
  • NP_001076585.1:p.His222Gln
  • NP_005032.2:p.His222Gln
  • LRG_94t1:c.666C>A
  • LRG_94:g.8721C>A
  • NC_000010.10:g.72358811G>T
  • NM_001083116.1:c.666C>A
Protein change:
H222Q
Links:
dbSNP: rs751247865
NCBI 1000 Genomes Browser:
rs751247865
Molecular consequence:
  • NM_001083116.3:c.666C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005041.6:c.666C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hemophagocytic lymphohistiocytosis (FHL)
Synonyms:
Hemophagocytic lymphohistiocytosis; Familial erythrophagocytic lymphohistiocytosis; Familial histiocytic reticulosis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015541; MedGen: C0272199; OMIM: PS267700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002103579Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Feb 15, 2022)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients.

An O, Gursoy A, Gurgey A, Keskin O.

Protein Sci. 2013 Jun;22(6):823-39. doi: 10.1002/pro.2265.

PubMed [citation]
PMID:
23592409
PMCID:
PMC3690721

Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer.

Chia J, Yeo KP, Whisstock JC, Dunstone MA, Trapani JA, Voskoboinik I.

Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9809-14. doi: 10.1073/pnas.0903815106. Epub 2009 Jun 1.

PubMed [citation]
PMID:
19487666
PMCID:
PMC2701033
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002103579.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: PRF1 c.666C>A (p.His222Gln) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249592 control chromosomes (gnomAD). c.666C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis and the variant segregated with the disease (examples: Karandikar_2007 and Vermeulen_2009, Voskoboinik_2005, Chia_2009). These data indicate that the variant is very likely to be associated with disease. Functional studies showed this variant results in normal expression of perforin but no detectable cytotoxic activity in transfected cells (Voskoboinik_2005, Chia_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Oct 8, 2024