ClinVar Genomic variation as it relates to human health
NM_000311.5(PRNP):c.538G>A (p.Val180Ile)
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.538G>A (p.Val180Ile)
Variation ID: 13405 Accession: VCV000013405.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p13 20: 4699758 (GRCh38) [ NCBI UCSC ] 20: 4680404 (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 14, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000311.5:c.538G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000302.1:p.Val180Ile missense NM_001080121.3:c.538G>A NP_001073590.1:p.Val180Ile missense NM_001080122.3:c.538G>A NP_001073591.1:p.Val180Ile missense NM_001080123.3:c.538G>A NP_001073592.1:p.Val180Ile missense NM_001271561.3:c.*227G>A 3 prime UTR NM_183079.4:c.538G>A NP_898902.1:p.Val180Ile missense NC_000020.11:g.4699758G>A NC_000020.10:g.4680404G>A NG_009087.1:g.18608G>A P04156:p.Val180Ile - Protein change
- V180I
- Other names
- PRNP, VAL180ILE (rs74315408)
- Canonical SPDI
- NC_000020.11:4699757: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
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
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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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
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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Apr 5, 2019 | RCV000020249.7 | |
Likely pathogenic (3) |
criteria provided, single submitter
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Mar 18, 2016 | RCV000014344.30 | |
Pathogenic, low penetrance (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV001212635.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV001807726.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2021 | RCV002476963.1 |
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
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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
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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Likely pathogenic
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Inherited Creutzfeldt-Jakob disease
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267463.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gerstmann-Straussler-Scheinker syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058948.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013405, PMID:8461023, PS1_S). TIn … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013405, PMID:8461023, PS1_S). TIn silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.624, 3CNET: 0.858, PP3_P). A missense variant is a common mechanism associated with Gerstmann-Straussler disease (PP2_P). herefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Spastic paraparesis (present)
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Pathogenic
(Nov 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inherited Creutzfeldt-Jakob disease
Gerstmann-Straussler-Scheinker syndrome Kuru, susceptibility to Fatal familial insomnia Huntington disease-like 1 Spongiform encephalopathy with neuropsychiatric features
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002788259.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic, low penetrance
(Dec 11, 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: SCV001384224.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 180 of the PRNP protein (p.Val180Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 180 of the PRNP protein (p.Val180Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Creutzfeldt-Jakob syndrome or prion disease (PMID: 8461023, 21269331, 22999564, 23555862, 25482600, 26791950). A large case control study reported that individuals carrying this variant have a life-time risk of developing prion disease of approximately 1% (PMID: 26791950). ClinVar contains an entry for this variant (Variation ID: 13405). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PRNP function (PMID: 17494694, 23132868, 23527023, 29382530). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the PRNP gene, it has been classified as Pathogenic (low penetrance). (less)
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Pathogenic
(Apr 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Genetic prion diseases
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914280.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PRNP c.538G>A (p.Val180Ile) missense variant is the most common pathogenic variant found in association with Creutzfeldt-Jacob disease (CJD) (Lee et al. 2016). Across a … (more)
The PRNP c.538G>A (p.Val180Ile) missense variant is the most common pathogenic variant found in association with Creutzfeldt-Jacob disease (CJD) (Lee et al. 2016). Across a selection of the available literature, the p.Val180Ile variant has been identified in a heterozygous state in at least 194 individuals with prion diseases and in one individual with CJD (Kitamoto et al. 1993; Chasseigneaux et al. 2006; Yang et al. 2010; Yoshida et al. 2010; Moe Lee et al. 2012; Higuma et al. 2013; Shi et al. 2014; Qina et al. 2014). Qina et al. (2014) also noted that only 11 out of 186 Japanese patients with the p.Val180Ile variant had a family history of dementia, suggesting that this variant may have reduced penetrance. Patients carrying the p.Val180Ile variant have a later onset of disease (late 70s), with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance as compared to classic CJD presentation (Qina et al. 2014). The p.Val180Ile variant was absent from 159 control individuals without neurological diseases from the above studies but is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. This frequency is unexpectedly high given the expected prevalence of this condition. Due to the large number of clinical cases with genetic prion diseases carrying this variant, this variant is classified as pathogenic for genetic prion diseases. However, the specific implications of this variant are somewhat uncertain given the later onset, milder presentation, and high population frequency that have been associated with this variant. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Feb 10, 2004)
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no assertion criteria provided
Method: literature only
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CREUTZFELDT-JAKOB DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034593.5
First in ClinVar: Apr 04, 2013 Last updated: Aug 09, 2019 |
Comment on evidence:
In a Japanese patient with Creutzfeldt-Jakob disease (CJD; 123400), Kitamoto et al. (1993) identified a mutation in the PRNP gene, resulting in a val180-to-ile (V180I) … (more)
In a Japanese patient with Creutzfeldt-Jakob disease (CJD; 123400), Kitamoto et al. (1993) identified a mutation in the PRNP gene, resulting in a val180-to-ile (V180I) substitution. The clinical course was similar to that caused by D178N (176640.0007), in which the average age of onset is about 9 years younger than that of CJD due to E200K (176640.0006). Jin et al. (2004) reported clinical features of 9 patients with CJD caused by the V180I mutation. None of the patients had a family history of dementia. Compared with 123 patients with sporadic CJD, the patients with the V180I mutation had an older age at onset, longer duration from the onset to the appearance of myoclonic jerks, akinesias, and mutism, and lower values of CSF neuron-specific enolase (NSE; 131360). None of the V180I patients presented with visual or cerebellar signs, but they did have more severe higher cortical dysfunction compared to sporadic CJD. MRI in the V180I patients showed disproportionately remarkable cortical lesions compared with the severity of clinical symptoms, and less remarkable basal ganglia lesions. Periodic sharp and wave complexes on EEG were not seen in any of the V180I patients. Jin et al. (2004) noted that patients with familial CJD caused by the V180I mutation often have no family history of the disease and that the unusual clinical features often lead to misdiagnosis. Minikel et al. (2016) assessed the impact of variants in PRNP on the risk of prion disease by analyzing large population control cohorts. They reported that the V180I variant shows low penetrance, with an estimated lifetime risk of 1%. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Inherited Creutzfeldt-Jakob disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040603.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
One of the five most common variants that account for 85% of genetic prion disease.
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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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Genetic Prion Disease. | Adam MP | - | 2021 | PMID: 20301407 |
Genetic Creutzfeldt-Jakob disease. | Ladogana A | Handbook of clinical neurology | 2018 | PMID: 29887139 |
Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene. | Ito Y | Biochemical and biophysical research communications | 2018 | PMID: 29382530 |
Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders. | Lee SM | PloS one | 2016 | PMID: 27341347 |
Quantifying prion disease penetrance using large population control cohorts. | Minikel EV | Science translational medicine | 2016 | PMID: 26791950 |
Rare V180I mutation in PRNP gene of a Chinese patient with Creutzfeldt-Jakob disease. | Shi Q | Prion | 2014 | PMID: 25482600 |
Clinical features of genetic Creutzfeldt-Jakob disease with V180I mutation in the prion protein gene. | Qina T | BMJ open | 2014 | PMID: 24838726 |
Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases. | Higuma M | PloS one | 2013 | PMID: 23555862 |
Glycoform-selective prion formation in sporadic and familial forms of prion disease. | Xiao X | PloS one | 2013 | PMID: 23527023 |
Familial Creutzfeldt-Jakob disease with a mutation at codon 180 presenting with an atypical phenotype. | Yeo MJ | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2013 | PMID: 22999564 |
Spreading brain lesions in a familial Creutzfeldt-Jakob disease with V180I mutation over 4 years. | Deguchi K | BMC neurology | 2012 | PMID: 23176099 |
Disease-associated mutations in the prion protein impair laminin-induced process outgrowth and survival. | Machado CF | The Journal of biological chemistry | 2012 | PMID: 23132868 |
Genotype patterns and characteristics of PRNP in the Korean population. | Moe Lee S | Prion | 2012 | PMID: 22561193 |
An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type. | Iwasaki Y | Neuropathology : official journal of the Japanese Society of Neuropathology | 2011 | PMID: 21269331 |
Familial Creutzfeldt-Jakob disease with V180I mutation. | Yang TI | Journal of Korean medical science | 2010 | PMID: 20592908 |
An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology. | Yoshida H | Neuropathology : official journal of the Japanese Society of Neuropathology | 2010 | PMID: 19703264 |
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 |
V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation. | Chasseigneaux S | Neuroscience letters | 2006 | PMID: 17029785 |
Clinical features of Creutzfeldt-Jakob disease with V180I mutation. | Jin K | Neurology | 2004 | PMID: 14872044 |
The effect of disease-associated mutations on the folding pathway of human prion protein. | Apetri AC | The Journal of biological chemistry | 2004 | PMID: 14761942 |
Novel missense variants of prion protein in Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. | Kitamoto T | Biochemical and biophysical research communications | 1993 | PMID: 8461023 |
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Text-mined citations for rs74315408 ...
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.