NM_001083116.3(PRF1):c.666C>A (p.His222Gln) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 1, 2023
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:: RCV000554706.6

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 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
SCV000644890	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14757862, 15205266, 16278825, 19595804, 15755897, 17525286, 19487666, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000644890

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (8)
[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

Unusual immunophenotype of CD8+ T cells in familial hemophagocytic lymphohistiocytosis.

Karandikar NJ, Kroft SH, Yegappan S, Rogers BB, Aquino VM, Lee KM, Kumar V, Guenaga FJ, Jaffe ES, Douek DC, McKenna RW.

Blood. 2004 Oct 1;104(7):2007-9. Epub 2004 Jun 17.

PubMed [citation]

PMID:: 15205266

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644890.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 222 of the PRF1 protein (p.His222Gln). This variant is present in population databases (rs751247865, gnomAD 0.01%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 14757862, 15205266, 16278825, 17525286, 19595804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 17525286, 19487666). 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: Oct 8, 2024

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