ClinVar Genomic variation as it relates to human health
NM_000311.5(PRNP):c.623G>A (p.Arg208His)
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_000311.5(PRNP):c.623G>A (p.Arg208His)
Variation ID: 13411 Accession: VCV000013411.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p13 20: 4699843 (GRCh38) [ NCBI UCSC ] 20: 4680489 (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 4, 2013 Feb 20, 2024 Aug 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000311.5:c.623G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000302.1:p.Arg208His missense NM_001080121.3:c.623G>A NP_001073590.1:p.Arg208His missense NM_001080122.3:c.623G>A NP_001073591.1:p.Arg208His missense NM_001080123.3:c.623G>A NP_001073592.1:p.Arg208His missense NM_001271561.3:c.*312G>A 3 prime UTR NM_183079.4:c.623G>A NP_898902.1:p.Arg208His missense NC_000020.11:g.4699843G>A NC_000020.10:g.4680489G>A NG_009087.1:g.18693G>A P04156:p.Arg208His - Protein change
- R208H
- Other names
- PRNP, ARG208HIS (rs74315412)
- Canonical SPDI
- NC_000020.11:4699842: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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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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PRNP | - | - |
GRCh38 GRCh37 |
171 | 206 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Uncertain significance (1) |
no assertion criteria provided
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Mar 1, 2006 | RCV000014352.27 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV001823096.3 | |
PRNP-related disorder
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Likely pathogenic (1) |
criteria provided, single submitter
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Nov 3, 2022 | RCV002468968.1 |
Pathogenic (1) |
criteria provided, single submitter
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Aug 17, 2023 | RCV001851853.4 |
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
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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
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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
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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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Likely pathogenic
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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PRNP-Related Disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766014.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: PRNP c.623G>A (p.Arg208His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PRNP c.623G>A (p.Arg208His) results in a non-conservative amino acid change in 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 6e-05 in 251464 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PRNP causing PRNP-Related Disorders (6e-05 vs ND), allowing no conclusion about variant significance. c.623G>A has been reported in the literature in individuals affected with PRNP related disorders such as Creutzfeldt-Jakob Disease confirmed in many cases by autopsy and histological findings (example: Basset-Leobon_2006, Caperllari_2005_Chen_2011 and Roeber_2005 etc.). These data indicate that the variant is likely to be associated with disease. It has also been reported in unaffected individuals (Chen_2011) as well as in patients with no family history, however, a low penetrance has been sugguested for this variant (example: Caperllari_2005). Several publications reports experimental evidence suggest that this variant affects PRNP protein function (example: Apetri_2004, Cardone_2014, Gerum_2010 and Liemann_1999) supporting a pathogenic role. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Mar 14, 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: SCV002072689.3
First in ClinVar: Feb 04, 2022 Last updated: Mar 26, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; As the variant is also observed in control populations, it may be … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; As the variant is also observed in control populations, it may be associated with reduced penetrance or may slightly increase prion disease risk (Minikel et la., 2016); This variant is associated with the following publications: (PMID: 21689662, 25450391, 25959220, 30898147, 15739100, 16533975, 10079068, 17494694, 14761942, 20541558, 22488860, 15753435, 21552571, 21791975, 20301407, 8909447, 23979103, 20855418, 26488179, 26791950, 32458274, 33917419, 34199205, 34487324, 34296847, 35888666, 36614069, 36285115, 35294674, 35813946, 35288744) (less)
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Pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Huntington disease-like 1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002294354.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRNP function (PMID: 10079068, 14761942, 17494694, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PRNP function (PMID: 10079068, 14761942, 17494694, 20541558, 25959220). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PRNP protein function. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 208 of the PRNP protein (p.Arg208His). This variant is present in population databases (rs74315412, gnomAD 0.03%). This missense change has been observed in individuals with genetic prion disease (PMID: 2458274, 8909447, 15739100, 15753435, 16533975). This variant is also known as R207H. ClinVar contains an entry for this variant (Variation ID: 13411). (less)
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Uncertain significance
(Mar 01, 2006)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034601.5
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2018 |
Comment on evidence:
This variant, previously titled CREUTZFELDT-JAKOB DISEASE, has been reclassified based on the report of Minikel et al. (2016). In a patient with pathologically confirmed CJD … (more)
This variant, previously titled CREUTZFELDT-JAKOB DISEASE, has been reclassified based on the report of Minikel et al. (2016). In a patient with pathologically confirmed CJD (123400), Mastrianni et al. (1996) identified a G-to-A transition in the PRNP gene, resulting in a nonconservative arg208-to-his (R208H) substitution. There was no family history of the disorder, but a younger unaffected family member also carried the R208H mutation. The mutation was not identified in 200 control alleles. Capellari et al. (2005) identified the R208H mutation in another patient with CJD who had no family history of the disorder. The patient was homozygous for met129 (176640.0005). She developed the disease at age 58; both parents had died of cancer at ages 69 and 52. Protein purification and mass spectrometry showed that the pathogenic PrP(Sc) protein derived from both the mutant and wildtype alleles. The authors suggested that the R208H mutation was de novo, showed reduced penetrance, or conferred susceptibility for the development of disease. Basset-Leobon et al. (2006) reported a 61-year-old man with familial CJD who had the R208H mutation, homozygosity for val129, and the type 2 protease-resistant prion protein. He had a long history of memory loss with behavioral and emotional disorders since childhood. The prion disease presented with aggressiveness, eating disorder, delirium, cerebellar ataxia, and cognitive decline, and progressed rapidly to akinetic mutism. He died 7 months after the onset of ataxia. Myoclonus was absent. EEG showed slow activity, and 14-3-3 CSF protein (see 113508) detection was negative. Neuropathologic examination showed severe spongiform changes in the frontal cortex, striatum, and thalamus, and kuru (245300)/amyloid-like plaques in the cerebellum and deep cortical layers of the frontal cortex. Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe, Inc. The R208H variant was found in 13 prion disease cases, 9 ExAC individuals, and 22 individuals in the 23andMe database. Given its high frequency in controls, the authors suggested that this variant may be benign or may slightly increase prion disease risk. (less)
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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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Quantifying prion disease penetrance using large population control cohorts. | Minikel EV | Science translational medicine | 2016 | PMID: 26791950 |
Structural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein. | Singh J | Angewandte Chemie (International ed. in English) | 2015 | PMID: 25959220 |
Mutant PrPCJD prevails over wild-type PrPCJD in the brain of V210I and R208H genetic Creutzfeldt-Jakob disease patients. | Cardone F | Biochemical and biophysical research communications | 2014 | PMID: 25450391 |
Genetic Creutzfeldt-Jakob disease with R208H mutation presenting as progressive supranuclear palsy. | Matěj R | Movement disorders : official journal of the Movement Disorder Society | 2012 | PMID: 22488860 |
The first Chinese case of Creutzfeldt-Jakob disease patient with R208H mutation in PRNP. | Chen C | Prion | 2011 | PMID: 21791975 |
Dynamic diagnosis of familial prion diseases supports the β2-α2 loop as a universal interference target. | Meli M | PloS one | 2011 | PMID: 21552571 |
The unfolded state of the murine prion protein and properties of single-point mutants related to human prion diseases. | Gerum C | Journal of molecular biology | 2010 | PMID: 20541558 |
Defective retrotranslocation causes loss of anti-Bax function in human familial prion protein mutants. | Jodoin J | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2007 | PMID: 17494694 |
Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques. | Basset-Leobon C | Archives of neurology | 2006 | PMID: 16533975 |
Genetic prion disease: the EUROCJD experience. | Kovács GG | Human genetics | 2005 | PMID: 16187142 |
Creutzfeldt-Jakob disease associated with the R208H mutation in the prion protein gene. | Capellari S | Neurology | 2005 | PMID: 15753435 |
Creutzfeldt-Jakob disease in a patient with an R208H mutation of the prion protein gene (PRNP) and a 17-kDa prion protein fragment. | Roeber S | Acta neuropathologica | 2005 | PMID: 15739100 |
The effect of disease-associated mutations on the folding pathway of human prion protein. | Apetri AC | The Journal of biological chemistry | 2004 | PMID: 14761942 |
Influence of amino acid substitutions related to inherited human prion diseases on the thermodynamic stability of the cellular prion protein. | Liemann S | Biochemistry | 1999 | PMID: 10079068 |
Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. | Mastrianni JA | Neurology | 1996 | PMID: 8909447 |
Commissural and intrinsic connections of the vestibular nuclei in the rabbit: a retrograde labeling study. | Epema AH | Experimental brain research | 1988 | PMID: 2458274 |
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Text-mined citations for rs74315412 ...
HelpRecord last updated Sep 29, 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.