NM_001083116.3(PRF1):c.797T>C (p.Ile266Thr) AND Familial hemophagocytic lymphohistiocytosis 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 1, 2021
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:: RCV001066139.7

Allele description [Variation Report for NM_001083116.3(PRF1):c.797T>C (p.Ile266Thr)]

NM_001083116.3(PRF1):c.797T>C (p.Ile266Thr)

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.797T>C (p.Ile266Thr)

HGVS:

NC_000010.11:g.70598924A>G
NG_009615.1:g.8852T>C
NM_001083116.3:c.797T>CMANE SELECT
NM_005041.6:c.797T>C
NP_001076585.1:p.Ile266Thr
NP_005032.2:p.Ile266Thr
LRG_94t1:c.797T>C
LRG_94:g.8852T>C
NC_000010.10:g.72358680A>G
NM_001083116.1:c.797T>C

Protein change:

I266T

Links:

dbSNP: rs763667216

NCBI 1000 Genomes Browser:

rs763667216

Molecular consequence:

NM_001083116.3:c.797T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005041.6:c.797T>C - 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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Rattus norvegicus eukaryotic elongation factor 2 lysine methyltransferase (Eef2k...
Rattus norvegicus eukaryotic elongation factor 2 lysine methyltransferase (Eef2kmt), mRNA
gi|157820552|ref|NM_001106975.1|

Nucleotide
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001231138	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26184781, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001231138

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2021)

germline

clinical testing

PubMed (2)
[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

Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations.

Tesi B, Chiang SC, El-Ghoneimy D, Hussein AA, Langenskiöld C, Wali R, Fadoo Z, Silva JP, Lecumberri R, Unal S, Nordenskjöld M, Bryceson YT, Henter JI, Meeths M.

Pediatr Blood Cancer. 2015 Dec;62(12):2094-100. doi: 10.1002/pbc.25646. Epub 2015 Jul 16.

PubMed [citation]

PMID:: 26184781

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001231138.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine with threonine at codon 266 of the PRF1 protein (p.Ile266Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs763667216, ExAC no frequency). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 26184781). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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