U.S. flag

An official website of the United States government

NM_001083116.3(PRF1):c.781G>A (p.Glu261Lys) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Dec 17, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001253459.5

Allele description [Variation Report for NM_001083116.3(PRF1):c.781G>A (p.Glu261Lys)]

NM_001083116.3(PRF1):c.781G>A (p.Glu261Lys)

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.781G>A (p.Glu261Lys)
HGVS:
  • NC_000010.11:g.70598940C>T
  • NG_009615.1:g.8836G>A
  • NM_001083116.3:c.781G>AMANE SELECT
  • NM_005041.6:c.781G>A
  • NP_001076585.1:p.Glu261Lys
  • NP_005032.2:p.Glu261Lys
  • LRG_94t1:c.781G>A
  • LRG_94:g.8836G>A
  • NC_000010.10:g.72358696C>T
  • NC_000010.10:g.72358696C>T
  • NM_001083116.1:c.781G>A
Protein change:
E261K
Links:
dbSNP: rs758110629
NCBI 1000 Genomes Browser:
rs758110629
Molecular consequence:
  • NM_001083116.3:c.781G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005041.6:c.781G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001429173Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 1, 2017) 		germlineclinical testing

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

SCV002249458Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 17, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis.

Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G.

Br J Haematol. 2002 Jun;117(4):965-72.

PubMed [citation]
PMID:
12060139
See all PubMed Citations (6)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429173.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002249458.3

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 261 of the PRF1 protein (p.Glu261Lys). This variant is present in population databases (rs758110629, gnomAD 0.003%). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 12060139, 31789783, 33746956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 976231). 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). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024