ClinVar Genomic variation as it relates to human health
NM_000311.5(PRNP):c.532G>A (p.Asp178Asn)
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.532G>A (p.Asp178Asn)
Variation ID: 39359 Accession: VCV000039359.68
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 20p13 20: 4699752 (GRCh38) [ NCBI UCSC ] 20: 4680398 (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 Oct 8, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000311.5:c.532G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000302.1:p.Asp178Asn missense NM_001080121.3:c.532G>A NP_001073590.1:p.Asp178Asn missense NM_001080122.3:c.532G>A NP_001073591.1:p.Asp178Asn missense NM_001080123.3:c.532G>A NP_001073592.1:p.Asp178Asn missense NM_001271561.3:c.*221G>A 3 prime UTR NM_183079.4:c.532G>A NP_898902.1:p.Asp178Asn missense NC_000020.11:g.4699752G>A NC_000020.10:g.4680398G>A NG_009087.1:g.18602G>A P04156:p.Asp178Asn - Protein change
- D178N
- Other names
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- Canonical SPDI
- NC_000020.11:4699751: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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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
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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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Likely pathogenic (2) |
criteria provided, single submitter
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- | RCV000020248.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV001214652.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV001200144.31 |
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
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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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Pathogenic
(Feb 06, 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: SCV003798935.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (Singh et al., 2015); Not observed at significant … (more)
Published functional studies demonstrate a damaging effect by accelerated misfolding and forming oligomers faster than wild-type protein (Singh et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32775516, 19996123, 1671440, 25959220, 16313190, 19571725, 10588836, 20872767, 25281825, 18062918, 10079068, 24118545, 23723004, 25473397, 20096809, 17494694, 14761942, 23132868, 9813003, 21689662, 23430483, 20038778, 21552571, 19543376, 22912570, 23276223, 19565837, 20104755, 15623717, 27056979, 26791950, 26074146, 17013786, 29569252, 9855529, 9270595, 9531435, 19228673, 29718878, 16227536, 10050890, 24340298, 32946318, 1439789, 8105681, 30012679, 10787305, 15459517, 33726816, 28549449) (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446468.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Insomnia (present)
Sex: male
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Huntington disease-like 1
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058395.1
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: VCV000039359, PMID:1671440, PS1_S). The … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039359, PMID:1671440, PS1_S). The variant was co-segregated with Gerstmann-Straussler disease in multiple affected family members with additional meioses (PMID: 10588836, 20038778) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 9531435, 16227536, 26488179, 9270595, PS4_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16313190, 23132868, PS3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.731, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Gerstmann-Straussler disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar ataxia (present) , Atypical behavior (present) , Broad-based gait (present) , Chorea (present) , Mental deterioration (present) , Diplopia (present) , Dystonic disorder (present) … (more)
Cerebellar ataxia (present) , Atypical behavior (present) , Broad-based gait (present) , Chorea (present) , Mental deterioration (present) , Diplopia (present) , Dystonic disorder (present) , Global brain atrophy (present) , Hand tremor (present) , Inability to walk (present) , Lower limb muscle weakness (present) , Parasomnia (present) , Seizure (present) , Status epilepticus (present) , Abnormal cerebral white matter morphology (present) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Fatal familial insomnia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004177277.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371026.23
First in ClinVar: Jul 16, 2020 Last updated: Oct 08, 2024 |
Comment:
PRNP: PS3:Very Strong, PS4, PM2
Number of individuals with the variant: 2
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Pathogenic
(Jan 25, 2024)
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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: SCV001386341.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the PRNP protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 178 of the PRNP protein (p.Asp178Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with genetic prion diseases (PMID: 1439789, 1671440, 9270595, 9531435, 10588836, 16227536, 17013786, 20038778, 26488179, 26791950). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39359). 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: 9813003, 16313190, 17494694, 23132868, 27350609). For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Fatal familial insomnia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000040602.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Associated with Fatal Familial Insomnia phenotype; 1 of the 5 most common variants that account for 85% of genetic prion disease when in cis with … (more)
Associated with Fatal Familial Insomnia phenotype; 1 of the 5 most common variants that account for 85% of genetic prion disease when in cis with Met129Val. (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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Genetic Prion Disease. | Adam MP | - | 2021 | PMID: 20301407 |
Genetic Creutzfeldt-Jakob disease. | Ladogana A | Handbook of clinical neurology | 2018 | PMID: 29887139 |
Towards authentic transgenic mouse models of heritable PrP prion diseases. | Watts JC | Acta neuropathologica | 2016 | PMID: 27350609 |
Quantifying prion disease penetrance using large population control cohorts. | Minikel EV | Science translational medicine | 2016 | PMID: 26791950 |
The Features of Genetic Prion Diseases Based on Chinese Surveillance Program. | Shi Q | PloS one | 2015 | PMID: 26488179 |
Disease-associated mutations in the prion protein impair laminin-induced process outgrowth and survival. | Machado CF | The Journal of biological chemistry | 2012 | PMID: 23132868 |
Discordant clinicopathologic phenotypes in a Japanese kindred of fatal familial insomnia. | Saitoh Y | Neurology | 2010 | PMID: 20038778 |
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 |
[Fatal familiar insomnia: clinical, neurophysiological and histopathological study of two cases]. | Ayuso Blanco T | Neurologia (Barcelona, Spain) | 2006 | PMID: 17013786 |
Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90-231. | Apetri AC | Biochemistry | 2005 | PMID: 16313190 |
Phenotypic variability in familial prion diseases due to the D178N mutation. | Zarranz JJ | Journal of neurology, neurosurgery, and psychiatry | 2005 | PMID: 16227536 |
Mutations of the prion protein gene phenotypic spectrum. | Kovács GG | Journal of neurology | 2002 | PMID: 12420099 |
Novel twelve-generation kindred of fatal familial insomnia from germany representing the entire spectrum of disease expression. | Harder A | American journal of medical genetics | 1999 | PMID: 10588836 |
Familial mutations and the thermodynamic stability of the recombinant human prion protein. | Swietnicki W | The Journal of biological chemistry | 1998 | PMID: 9813003 |
Identification in Israel of 2 Jewish Creutzfeld-Jakob disease patients with a 178 mutation at their PrP gene. | Rosenmann H | Acta neurologica Scandinavica | 1998 | PMID: 9531435 |
The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred. | McLean CA | Neurology | 1997 | PMID: 9270595 |
Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism. | Goldfarb LG | Science (New York, N.Y.) | 1992 | PMID: 1439789 |
New mutation in scrapie amyloid precursor gene (at codon 178) in Finnish Creutzfeldt-Jakob kindred. | Goldfarb LG | Lancet (London, England) | 1991 | PMID: 1671440 |
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Text-mined citations for rs74315403 ...
HelpRecord last updated Oct 08, 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.