ClinVar Genomic variation as it relates to human health
NM_001083116.3(PRF1):c.445G>A (p.Gly149Ser)
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.445G>A (p.Gly149Ser)
Variation ID: 520942 Accession: VCV000520942.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 70600458 (GRCh38) [ NCBI UCSC ] 10: 72360214 (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 Apr 15, 2018 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001083116.3:c.445G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001076585.1:p.Gly149Ser missense NM_005041.6:c.445G>A NP_005032.2:p.Gly149Ser missense NC_000010.11:g.70600458C>T NC_000010.10:g.72360214C>T NG_009615.1:g.7318G>A LRG_94:g.7318G>A LRG_94t1:c.445G>A - Protein change
- G149S
- Other names
- p.Gly149Ser
- Canonical SPDI
- NC_000010.11:70600457:C:T
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00014
The Genome Aggregation Database (gnomAD), exomes 0.00014
Trans-Omics for Precision Medicine (TOPMed) 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 |
662 | 679 |
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 (1) |
criteria provided, single submitter
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Mar 2, 2016 | RCV000622519.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000819599.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 20, 2020 | RCV001331590.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2023 | RCV002473073.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2022 | RCV002483745.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2023 | RCV003479176.1 |
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
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001138066.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Mar 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741303.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Developmental regression (present) , Seizures (present) , Muscular hypotonia (present) , Respiratory distress (present) , Feeding difficulties (present) , Encephalitis (present) , Myelitis (present)
Sex: male
Ethnicity/Population group: Hispanic/Italian
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Pathogenic
(Jan 30, 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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Invitae
Accession: SCV000960267.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 149 of the PRF1 protein (p.Gly149Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 149 of the PRF1 protein (p.Gly149Ser). This variant is present in population databases (rs147462227, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of hemophagocytic lymphohistiocytosis (PMID: 16278825, 17873118, 21959744, 26184781; externalcommunication). 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: 520942). 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: 16374518). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Aplastic anemia
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001523660.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID: 15755897, 19487666, 23592409, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID: 15755897, 19487666, 23592409, 11179007, ClinVar ID: 802584 for c.148G>A (p.V50M); PMID: 21959744, 23073290, 23592409, 11756153, 19487666, 21881043, 27577878, 15755897, 24916509, ClinVar ID: 520942 for c.445G>A (p.G149S)] (less)
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Pathogenic
(Dec 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
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Genomics Facility, Ludwig-Maximilians-Universität München
Accession: SCV002073891.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Clinical Features:
Hemophagocytosis (present) , Lymphocytosis (present)
Age: 0-9 years
Sex: female
Tissue: PBMCs
Method: Agilent V6+UTR exome enrichment, Illumina NextSeq 500 sequencing
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Pathogenic
(Jan 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis 2
Lymphoma, non-Hodgkin, familial Aplastic anemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002777246.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002770374.2
First in ClinVar: Dec 31, 2022 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect including reduced expression and absence of cytotoxic activity (Voskoboinik et al., 2005); In silico analysis supports that this … (more)
Published functional studies demonstrate a damaging effect including reduced expression and absence of cytotoxic activity (Voskoboinik et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21881043, 21959744, 24916509, 23073290, 17873118, 23592409, 19487666, 16374518, 11756153, 26184781, 16278825, 27577878, 33694335, 31589614, 34308104, 25297583, 32542393, 15755897, 36440336) (less)
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Pathogenic
(Nov 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hemophagocytic lymphohistiocytosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223335.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PRF1 c.445G>A (p.Gly149Ser) results in a non-conservative amino acid change located in the membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded … (more)
Variant summary: PRF1 c.445G>A (p.Gly149Ser) results in a non-conservative amino acid change located in the membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251436 control chromosomes, predominantly at a frequency of 0.00064 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00014 vs 0.0027), allowing no conclusion about variant significance. c.445G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (e.g. Voskoboinik_2005). The variant had little to no detectable protein expression compared to WT perforin and had minimal detectable cytotoxic activity in a cell-based assay. The following publications have been ascertained in the context of this evaluation (PMID: 11756153, 14757862, 15755897, 17873118). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 15, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226836.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM3, PS3, PS4_moderate
Number of individuals with the variant: 1
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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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Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders. | Gadoury-Levesque V | Blood advances | 2020 | PMID: 32542393 |
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations. | Tesi B | Pediatric blood & cancer | 2015 | PMID: 26184781 |
Synergistic defects of different molecules in the cytotoxic pathway lead to clinical familial hemophagocytic lymphohistiocytosis. | Zhang K | Blood | 2014 | PMID: 24916509 |
Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. | An O | Protein science : a publication of the Protein Society | 2013 | PMID: 23592409 |
Functional impact of A91V mutation of the PRF1 perforin gene. | Martínez-Pomar N | Human immunology | 2013 | PMID: 23073290 |
Familial hemophagocytic lymphohistiocytosis in a pediatric patient diagnosed by brain magnetic resonance imaging. | van Egmond ME | Neuropediatrics | 2011 | PMID: 21959744 |
Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. | Zhang K | Blood | 2011 | PMID: 21881043 |
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 |
Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis due to perforin mutations. | Trizzino A | Journal of medical genetics | 2008 | PMID: 17873118 |
Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis. | Risma KA | The Journal of clinical investigation | 2006 | PMID: 16374518 |
Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A. | Zur Stadt U | Human mutation | 2006 | PMID: 16278825 |
A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. | Voskoboinik I | Blood | 2005 | PMID: 15755897 |
Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. | Molleran Lee S | Journal of medical genetics | 2004 | PMID: 14757862 |
Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. | Kogawa K | Blood | 2002 | PMID: 11756153 |
Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis. | Göransdotter Ericson K | American journal of human genetics | 2001 | PMID: 11179007 |
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Text-mined citations for rs147462227 ...
HelpRecord last updated Feb 20, 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.