NM_001083116.3(PRF1):c.836G>A (p.Cys279Tyr) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 8, 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:: RCV000014714.29

Allele description [Variation Report for NM_001083116.3(PRF1):c.836G>A (p.Cys279Tyr)]

NM_001083116.3(PRF1):c.836G>A (p.Cys279Tyr)

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.836G>A (p.Cys279Tyr)

HGVS:

NC_000010.11:g.70598885C>T
NG_009615.1:g.8891G>A
NM_001083116.3:c.836G>AMANE SELECT
NM_005041.6:c.836G>A
NP_001076585.1:p.Cys279Tyr
NP_005032.2:p.Cys279Tyr
LRG_94:g.8891G>A
NC_000010.10:g.72358641C>T
P14222:p.Cys279Tyr

Protein change:

C279Y; CYS279TYR

Links:

UniProtKB: P14222#VAR_010747; OMIM: 170280.0007; dbSNP: rs104894182

NCBI 1000 Genomes Browser:

rs104894182

Molecular consequence:

NM_001083116.3:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005041.6:c.836G>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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cadherin-9 precursor [Rattus norvegicus]
cadherin-9 precursor [Rattus norvegicus]
gi|274323464|ref|NP_001162101.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034969	OMIM	no assertion criteria provided	Pathogenic (Dec 3, 1999)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004294731	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15755897, 10583959, 12060139, 17627755, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034969

OMIM

no assertion criteria provided

Pathogenic
(Dec 3, 1999)

germline

literature only

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

SCV004294731

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis.

Voskoboinik I, Thia MC, Trapani JA.

Blood. 2005 Jun 15;105(12):4700-6. Epub 2005 Mar 8.

PubMed [citation]

PMID:: 15755897

Perforin gene defects in familial hemophagocytic lymphohistiocytosis.

Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint Basile G, Kumar V.

Science. 1999 Dec 3;286(5446):1957-9.

PubMed [citation]

PMID:: 10583959

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000034969.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified compound heterozygosity for mutations in the PRF1 gene: an 836C-A transversion, resulting in a cys279-to-tyr (C279Y) substitution, and a 548T-G transversion, resulting in a val183-to-gly (V183G; 170280.0008) substitution.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294731.1

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897). 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. ClinVar contains an entry for this variant (Variation ID: 13714). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 10583959, 12060139, 17627755; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs104894182, gnomAD 0.004%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 279 of the PRF1 protein (p.Cys279Tyr).

#	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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