ClinVar Genomic variation as it relates to human health
NM_001083116.3(PRF1):c.1349C>T (p.Thr450Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001083116.3(PRF1):c.1349C>T (p.Thr450Met)
Variation ID: 468301 Accession: VCV000468301.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 70598372 (GRCh38) [ NCBI UCSC ] 10: 72358128 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 26, 2018 Apr 6, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001083116.3:c.1349C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001076585.1:p.Thr450Met missense NM_005041.5:c.1349C>T NM_005041.6:c.1349C>T NP_005032.2:p.Thr450Met missense NC_000010.11:g.70598372G>A NC_000010.10:g.72358128G>A NG_009615.1:g.9404C>T LRG_94:g.9404C>T LRG_94t1:c.1349C>T - Protein change
- T450M
- Other names
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- Canonical SPDI
- NC_000010.11:70598371:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PRF1 | - | - |
GRCh38 GRCh37 |
659 | 676 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000547072.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2019 | RCV001783053.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV003476292.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 26, 2019)
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criteria provided, single submitter
Method: research
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Familial hemophagocytic lymphohistiocytosis 2
Affected status: yes
Allele origin:
unknown
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV000993625.1 First in ClinVar: Sep 26, 2019 Last updated: Sep 26, 2019 |
Number of individuals with the variant: 1
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aplastic anemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204180.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Jan 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024742.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000644878.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 450 of the PRF1 protein (p.Thr450Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 450 of the PRF1 protein (p.Thr450Met). This variant is present in population databases (rs189650890, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 15632205, 15728124, 17266056, 18074390, 20092789, 21152410, 21881043, 25233452, 25297583, 26903364). 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: 468301). 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: 15632205, 19487666). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis 2
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004808173.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Previously undiagnosed fatal familial haemophagocytic lymphohistiocytosis in a 24-year-old woman. | Barmettler S | BMJ case reports | 2016 | PMID: 26903364 |
[Analysis of clinical phenotype and genetic mutations of a pedigree of familial hemophagocytic lymphohistiocytosis]. | Sun S | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2014 | PMID: 25297583 |
Genetic features of late onset primary hemophagocytic lymphohistiocytosis in adolescence or adulthood. | Wang Y | PloS one | 2014 | PMID: 25233452 |
Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. | Zhang K | Blood | 2011 | PMID: 21881043 |
Subtypes of familial hemophagocytic lymphohistiocytosis in Japan based on genetic and functional analyses of cytotoxic T lymphocytes. | Nagai K | PloS one | 2010 | PMID: 21152410 |
Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis. | Lu G | Chinese medical journal | 2009 | PMID: 20092789 |
Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. | Chia J | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19487666 |
A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency. | Beaty AD | Pediatric blood & cancer | 2008 | PMID: 18074390 |
Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. | Ueda I | American journal of hematology | 2007 | PMID: 17266056 |
A proportion of patients with lymphoma may harbor mutations of the perforin gene. | Clementi R | Blood | 2005 | PMID: 15728124 |
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. | Ishii E | Blood | 2005 | PMID: 15632205 |
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Text-mined citations for rs189650890 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.