NM_001083116.3(PRF1):c.1267C>T (p.Gln423Ter) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 18, 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:: RCV001963228.4

Allele description [Variation Report for NM_001083116.3(PRF1):c.1267C>T (p.Gln423Ter)]

NM_001083116.3(PRF1):c.1267C>T (p.Gln423Ter)

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.1267C>T (p.Gln423Ter)

HGVS:

NC_000010.11:g.70598454G>A
NG_009615.1:g.9322C>T
NM_001083116.3:c.1267C>TMANE SELECT
NM_005041.6:c.1267C>T
NP_001076585.1:p.Gln423Ter
NP_005032.2:p.Gln423Ter
LRG_94:g.9322C>T
NC_000010.10:g.72358210G>A

Protein change:

Q423*

Links:

dbSNP: rs768953378

NCBI 1000 Genomes Browser:

rs768953378

Molecular consequence:

NM_001083116.3:c.1267C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_005041.6:c.1267C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002246614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25326637, 26450956, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002246614

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (3)
[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

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

Accuracy of flow cytometric perforin screening for detecting patients with FHL due to PRF1 mutations.

Abdalgani M, Filipovich AH, Choo S, Zhang K, Gifford C, Villanueva J, Bleesing JJ, Marsh RA.

Blood. 2015 Oct 8;126(15):1858-60. doi: 10.1182/blood-2015-06-648659. No abstract available.

PubMed [citation]

PMID:: 26450956
PMCID:: PMC4828082

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002246614.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Gln423*) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 133 amino acid(s) of the PRF1 protein. This variant is present in population databases (rs768953378, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1460060). This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Gln446Pro) have been determined to be pathogenic (PMID: 25326637, 26450956). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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: Sep 29, 2024

ClinVar

Relating variation to medicine