ClinVar Genomic variation as it relates to human health
NM_000021.4(PSEN1):c.488A>G (p.His163Arg)
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
-
NM_000021.4(PSEN1):c.488A>G (p.His163Arg)
Variation ID: 18124 Accession: VCV000018124.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 14q24.2 14: 73186860 (GRCh38) [ NCBI UCSC ] 14: 73653568 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Feb 20, 2014 Feb 28, 2024 Aug 30, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000021.4:c.488A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000012.1:p.His163Arg missense NM_007318.3:c.476A>G NP_015557.2:p.His159Arg missense NC_000014.9:g.73186860A>G NC_000014.8:g.73653568A>G NG_007386.2:g.55390A>G LRG_224:g.55390A>G LRG_224t1:c.488A>G LRG_224p1:p.His163Arg P49768:p.His163Arg - Protein change
- H163R, H159R
- Other names
- -
- Canonical SPDI
- NC_000014.9:73186859:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
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
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
PSEN1 | - | - |
GRCh38 GRCh37 |
514 | 531 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Jun 29, 1995 | RCV000019752.30 | |
Pathogenic (2) |
criteria provided, single submitter
|
Nov 15, 2022 | RCV000084318.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 29, 2021 | RCV000534810.6 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 30, 2023 | RCV003407347.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 12, 2021 | RCV002490394.2 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Nov 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Pick disease
Frontotemporal dementia Alzheimer disease 3 Dilated cardiomyopathy 1U Acne inversa, familial, 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002802873.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PSEN1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004108245.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PSEN1 c.488A>G variant is predicted to result in the amino acid substitution p.His163Arg. This variant has previously been reported to be causative for Alzheimer … (more)
The PSEN1 c.488A>G variant is predicted to result in the amino acid substitution p.His163Arg. This variant has previously been reported to be causative for Alzheimer disease in many unrelated individuals (Sherrington et al. 1995. PubMed ID: 7596406; Lohmann et al. 2012. PubMed ID: 22503161). Internally, we have observed this variant in other patients with PSEN1-related disorders. Of note, two different missense variants c.487C>T (p.His163Tyr) and c.488A>C (p.His163Pro), affecting the same amino acid residue, have also been reported to be causative for Alzheimer disease (Alzheimer's Disease Collaborative Group. 1995. PubMed ID: 7550356; HGMD database). Functional studies suggested this variant reduced both Aß40 and Aß42 production, but increased Aß42/Aß 40 ratio through the effect on ?-secretase (Placanica et al. 2009. PubMed ID: 19036728; Sun et al. 2017. PubMed ID: 27930341). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, we classify this variant as pathogenic. (less)
|
|
Pathogenic
(Nov 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease 3
Pick disease Acne inversa, familial, 3 Frontotemporal dementia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000639607.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This missense change has been observed in individual(s) with early-onset Alzheimer's disease (EOAD) (PMID: 7596406, 8733303, 12433263, 22503161, 26337232, 27264813). It has also been observed … (more)
This missense change has been observed in individual(s) with early-onset Alzheimer's disease (EOAD) (PMID: 7596406, 8733303, 12433263, 22503161, 26337232, 27264813). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 163 of the PSEN1 protein (p.His163Arg). ClinVar contains an entry for this variant (Variation ID: 18124). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 8986743, 19111578, 22461631). 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 expected to disrupt PSEN1 protein function. (less)
|
|
Pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV004229914.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features associated with Alzheimer disease or dementia. This variant has not been reported in … (more)
This variant has been identified in multiple unrelated individuals with clinical features associated with Alzheimer disease or dementia. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10327206, 12549925, 18045903) (less)
|
|
Pathogenic
(Jun 29, 1995)
|
no assertion criteria provided
Method: literature only
|
ALZHEIMER DISEASE, FAMILIAL, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000040050.3
First in ClinVar: Apr 04, 2013 Last updated: May 15, 2017 |
Comment on evidence:
In an American pedigree with chromosome 14-linked Alzheimer disease (AD3; 607822), Sherrington et al. (1995) found a mutation in the PSEN1 gene, resulting in a … (more)
In an American pedigree with chromosome 14-linked Alzheimer disease (AD3; 607822), Sherrington et al. (1995) found a mutation in the PSEN1 gene, resulting in a his163-to-arg (H163R) substitution. The same mutation was found in a small French Canadian pedigree with early-onset Alzheimer disease. (less)
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
|
VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116454.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_20
|
|
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 |
---|---|---|---|---|
A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences. | Shea YF | Journal of the Formosan Medical Association = Taiwan yi zhi | 2016 | PMID: 26337232 |
Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. | Shi Z | Dementia and geriatric cognitive disorders | 2015 | PMID: 25323700 |
Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. | Liu Q | JAMA neurology | 2014 | PMID: 25285942 |
Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing. | Yagi R | Neurobiology of aging | 2014 | PMID: 24559647 |
Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. | Ikeda M | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2013 | PMID: 23638752 |
Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology. | Roh JH | Science translational medicine | 2012 | PMID: 22956200 |
Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. | Lohmann E | Neurobiology of aging | 2012 | PMID: 22503161 |
The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. | Wallon D | Journal of Alzheimer's disease : JAD | 2012 | PMID: 22475797 |
Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase. | Chau DM | The Journal of biological chemistry | 2012 | PMID: 22461631 |
Conformational altered p53 as an early marker of oxidative stress in Alzheimer's disease. | Buizza L | PloS one | 2012 | PMID: 22242180 |
Presenilin/γ-secretase regulates neurexin processing at synapses. | Saura CA | PloS one | 2011 | PMID: 21559374 |
Clinical-genetic correlations in familial Alzheimer's disease caused by presenilin 1 mutations. | Gómez-Tortosa E | Journal of Alzheimer's disease : JAD | 2010 | PMID: 20157243 |
The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42 production in the central nervous system. | Yanagida K | EMBO molecular medicine | 2009 | PMID: 20049724 |
Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease. | Bojarski L | Biochimica et biophysica acta | 2009 | PMID: 19111578 |
Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease. | Kaneko H | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2007 | PMID: 18045903 |
Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. | Zekanowski C | Experimental neurology | 2003 | PMID: 14769392 |
Distinct mechanisms by mutant presenilin 1 and 2 leading to increased intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. | Qi Y | Biochemistry | 2003 | PMID: 12549925 |
Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. | Lleó A | Archives of neurology | 2002 | PMID: 12433263 |
Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. | Rogaeva EA | Neurology | 2001 | PMID: 11524469 |
Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. | Murayama O | Neuroscience letters | 1999 | PMID: 10327206 |
Familial Alzheimer's disease genes in Japanese. | Kamimura K | Journal of the neurological sciences | 1998 | PMID: 9804121 |
Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. | Poorkaj P | Human mutation | 1998 | PMID: 9521423 |
Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. | Citron M | Nature medicine | 1997 | PMID: 8986743 |
Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. | Levitan D | Proceedings of the National Academy of Sciences of the United States of America | 1996 | PMID: 8962160 |
A presenilin 1 mutation in an early onset Alzheimer's family: no association with presenilin 2. | Poduslo SE | Neuroreport | 1996 | PMID: 8905716 |
Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families. | Kamino K | Neuroscience letters | 1996 | PMID: 8733303 |
Mutation analysis of presenillin 1 gene in Alzheimer's disease. | Boteva K | Lancet (London, England) | 1996 | PMID: 8538334 |
Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. | Campion D | Human molecular genetics | 1995 | PMID: 8634712 |
Missense mutation of S182 gene in Japanese familial Alzheimer's disease. | Tanahashi H | Lancet (London, England) | 1995 | PMID: 7623585 |
Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. | Sherrington R | Nature | 1995 | PMID: 7596406 |
click to load more click to collapse |
Text-mined citations for rs63750590 ...
HelpRecord last updated May 19, 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.