ClinVar Genomic variation as it relates to human health
NM_000021.4(PSEN1):c.428T>C (p.Ile143Thr)
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_000021.4(PSEN1):c.428T>C (p.Ile143Thr)
Variation ID: 98026 Accession: VCV000098026.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.2 14: 73173655 (GRCh38) [ NCBI UCSC ] 14: 73640363 (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 Feb 20, 2014 Apr 15, 2024 Sep 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000021.4:c.428T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000012.1:p.Ile143Thr missense NM_007318.3:c.416T>C NP_015557.2:p.Ile139Thr missense NC_000014.9:g.73173655T>C NC_000014.8:g.73640363T>C NG_007386.2:g.42185T>C LRG_224:g.42185T>C LRG_224t1:c.428T>C LRG_224p1:p.Ile143Thr P49768:p.Ile143Thr - Protein change
- I143T, I139T
- Other names
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- Canonical SPDI
- NC_000014.9:73173654:T:C
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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.
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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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PSEN1 | - | - |
GRCh38 GRCh37 |
522 | 539 |
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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Pathogenic (2) |
criteria provided, single submitter
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Feb 1, 2016 | RCV000084308.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 13, 2023 | RCV001071503.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2022 | RCV003993799.1 |
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
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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 01, 2016)
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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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Athena Diagnostics
Accession: SCV000614821.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
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Pathogenic
(Sep 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001236811.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 98026). This missense change has been observed in individuals with early-onset Alzheimer's disease (PMID: 8634711, 17968601, … (more)
ClinVar contains an entry for this variant (Variation ID: 98026). This missense change has been observed in individuals with early-onset Alzheimer's disease (PMID: 8634711, 17968601, 20628413, 24773620, 28350801, 30090657, 30528841). 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 143 of the PSEN1 protein (p.Ile143Thr). 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. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 19276550, 19276551, 22508690, 27930341). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alzheimer disease 3
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812496.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in PSEN1 is predicted to replace isoleucine with threonine at codon 143, p.(Ile143Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in PSEN1 is predicted to replace isoleucine with threonine at codon 143, p.(Ile143Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in Transmembrane-II domain. There is a moderate physicochemical difference between isoleucine and threonine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in various probands/families internationally with early-onset Alzheimer's disease (EOAD) and segregates with disease in multiple families (PMID: 8634711, 11568920, 17968601, 20628413, 30090657). The variant deregulates neurite growth in functional assays and significantly reduces brain glucosylceramide and gangliosides in a knock-in mouse model, similarly to human EOAD patients (PMID: 11157069, 22508690). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Moderate, PS4_Moderate, PM2_Supporting, PP3. (less)
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116444.1
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_2
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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 analysis of neurodegenerative diseases in a pathology cohort. | Blauwendraat C | Neurobiology of aging | 2019 | PMID: 30528841 |
The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. | Xu Y | Aging and disease | 2018 | PMID: 30090657 |
APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. | Lanoiselée HM | PLoS medicine | 2017 | PMID: 28350801 |
Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. | Sun L | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 27930341 |
Preclinical cerebrospinal fluid and volumetric magnetic resonance imaging biomarkers in Swedish familial Alzheimer's disease. | Thordardottir S | Journal of Alzheimer's disease : JAD | 2015 | PMID: 25182737 |
U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21. | Hales CM | Molecular neurodegeneration | 2014 | PMID: 24773620 |
The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease. | Sandebring A | PloS one | 2013 | PMID: 23409063 |
Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis. | Mutoh T | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2012 | PMID: 22508690 |
Potent amyloidogenicity and pathogenicity of Aβ43. | Saito T | Nature neuroscience | 2011 | PMID: 21725313 |
The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions. | Keller L | European journal of human genetics : EJHG | 2010 | PMID: 20628413 |
Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. | Welander H | Journal of neurochemistry | 2009 | PMID: 19457079 |
Increase in p53 protein levels by presenilin 1 gene mutations and its inhibition by secretase inhibitors. | Ma L | Journal of Alzheimer's disease : JAD | 2009 | PMID: 19276551 |
Enhancement of activation of caspases by presenilin 1 gene mutations and its inhibition by secretase inhibitors. | Miyoshi K | Journal of Alzheimer's disease : JAD | 2009 | PMID: 19276550 |
Familial cases presenting very early onset autosomal dominant Alzheimer's disease with I143T in presenilin-1 gene: implication for genotype-phenotype correlation. | Arai N | Neurogenetics | 2008 | PMID: 17968601 |
Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. | Kumar-Singh S | Human mutation | 2006 | PMID: 16752394 |
Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. | Raux G | Journal of medical genetics | 2005 | PMID: 16033913 |
Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. | Pigino G | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2003 | PMID: 12805290 |
Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. | Arango D | American journal of medical genetics | 2001 | PMID: 11568920 |
Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. | Rogaeva EA | Neurology | 2001 | PMID: 11524469 |
Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation. | Pigino G | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2001 | PMID: 11157069 |
Proteolytic processing of presenilin-1 in human lymphoblasts is not affected by the presence of the I143T and G384A mutations. | Vanderhoeven I | Neuroscience letters | 1999 | PMID: 10548420 |
Evidence that Abeta42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. | De Jonghe C | Neurobiology of disease | 1999 | PMID: 10448055 |
No influence of presenilin1 I143T and G384A mutations on endogenous tau phosphorylation in human and mouse neuroblastoma cells. | Julliams A | Neuroscience letters | 1999 | PMID: 10430510 |
Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. | Murayama O | Neuroscience letters | 1999 | PMID: 10327206 |
Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. | Cruts M | Human molecular genetics | 1995 | PMID: 8634711 |
Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3. | Cruts M | Human molecular genetics | 1995 | PMID: 7581374 |
Early-onset Alzheimer's disease in 2 large Belgian families. | Martin JJ | Neurology | 1991 | PMID: 1985297 |
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Text-mined citations for rs63750004 ...
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.