The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools predict that this variant is damaging.
ClinVar Genomic variation as it relates to human health
NM_000021.4(PSEN1):c.806G>A (p.Arg269His)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000021.4(PSEN1):c.806G>A (p.Arg269His)
Variation ID: 38297 Accession: VCV000038297.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.2 14: 73198067 (GRCh38) [ NCBI UCSC ] 14: 73664775 (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 Apr 4, 2013 Oct 20, 2024 Jan 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000021.4:c.806G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000012.1:p.Arg269His missense NM_007318.3:c.794G>A NP_015557.2:p.Arg265His missense NC_000014.9:g.73198067G>A NC_000014.8:g.73664775G>A NG_007386.2:g.66597G>A LRG_224:g.66597G>A LRG_224t1:c.806G>A LRG_224p1:p.Arg269His P49768:p.Arg269His - Protein change
- R269H, R265H
- Other names
- -
- Canonical SPDI
- NC_000014.9:73198066:G:A
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 |
525 | 542 | |
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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000031858.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 18, 2022 | RCV000084374.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 31, 2024 | RCV000689465.11 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002770536.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been … (more)
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools predict that this variant is damaging. (less)
|
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Pathogenic
(Jan 31, 2024)
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000817117.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the PSEN1 protein (p.Arg269His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the PSEN1 protein (p.Arg269His). 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 Alzheimer's disease (PMID: 9189043, 9804121, 27777022, 28350801; Invitae). ClinVar contains an entry for this variant (Variation ID: 38297). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg269 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8910898, 15205973, 27930341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248748.24
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
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not provided
(-)
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no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
unknown
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VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116510.1
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_37
|
|
|
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not provided
(-)
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no classification provided
Method: literature only
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Alzheimer disease 4
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000054464.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the PSEN1 protein (p.Arg269His). 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 Alzheimer's disease (PMID: 9189043, 9804121, 27777022, 28350801; Invitae). ClinVar contains an entry for this variant (Variation ID: 38297). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg269 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8910898, 15205973, 27930341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools predict that this variant is damaging.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 269 of the PSEN1 protein (p.Arg269His). 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 Alzheimer's disease (PMID: 9189043, 9804121, 27777022, 28350801; Invitae). ClinVar contains an entry for this variant (Variation ID: 38297). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg269 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8910898, 15205973, 27930341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The role of genetics in neurodegenerative dementia: a large cohort study in South China. | Jiao B | NPJ genomic medicine | 2021 | PMID: 34389718 |
| Amyloid-β(1-43) cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. | Perrone F | Alzheimer's research & therapy | 2020 | PMID: 32917274 |
| Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators. | Petit D | The EMBO journal | 2019 | PMID: 31109937 |
| Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. | Jiang B | Neurobiology of aging | 2019 | PMID: 30598257 |
| Genetic analysis of neurodegenerative diseases in a pathology cohort. | Blauwendraat C | Neurobiology of aging | 2019 | PMID: 30528841 |
| Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network. | Karch CM | Alzheimer's research & therapy | 2018 | PMID: 30045758 |
| Identification of missing variants by combining multiple analytic pipelines. | Ren Y | BMC bioinformatics | 2018 | PMID: 29661148 |
| Impairment of memory generalization in preclinical autosomal dominant Alzheimer's disease mutation carriers. | Petok JR | Neurobiology of aging | 2018 | PMID: 29494861 |
| 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 |
| Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. | Ryan NS | The Lancet. Neurology | 2016 | PMID: 27777022 |
| Processing of Self versus Non-Self in Alzheimer's Disease. | Bond RL | Frontiers in human neuroscience | 2016 | PMID: 27014028 |
| Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease. | Ryan NS | Neurobiology of aging | 2015 | PMID: 26410308 |
| Mutation frequency of PRKAR1B and the major familial dementia genes in a Dutch early onset dementia cohort. | Cohn-Hokke PE | Journal of neurology | 2014 | PMID: 25108559 |
| Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer's disease. | Ryan NS | Brain : a journal of neurology | 2013 | PMID: 23539189 |
| Early-Onset Familial Alzheimer Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2012 | PMID: 20301414 |
| The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. | Larner AJ | Journal of the neurological sciences | 2007 | PMID: 17188713 |
| Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. | Larner AJ | Journal of neurology | 2006 | PMID: 16267640 |
| Prominent behavioural and psychiatric symptoms in early-onset Alzheimer's disease in a sib pair with the presenilin-1 gene R269G mutation. | Doran M | European archives of psychiatry and clinical neuroscience | 2004 | PMID: 15205973 |
| Amino- and carboxyl-terminal mutants of presenilin 1 cause neuronal cell death through distinct toxic mechanisms: Study of 27 different presenilin 1 mutants. | Hashimoto Y | Journal of neuroscience research | 2004 | PMID: 14743455 |
| Early onset familial Alzheimer's disease: Mutation frequency in 31 families. | Janssen JC | Neurology | 2003 | PMID: 12552037 |
| Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease. | Mann DM | The American journal of pathology | 2001 | PMID: 11395394 |
| The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. | Gómez-Isla T | Brain : a journal of neurology | 1999 | PMID: 10468510 |
| Familial Alzheimer's disease genes in Japanese. | Kamimura K | Journal of the neurological sciences | 1998 | PMID: 9804121 |
| Interaction of presenilins with the filamin family of actin-binding proteins. | Zhang W | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1998 | PMID: 9437013 |
| A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. | Gómez-Isla T | Annals of neurology | 1997 | PMID: 9189043 |
| A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. | Perez-Tur J | Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration | 1996 | PMID: 8910898 |
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Text-mined citations for rs63750900 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.