This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341).
ClinVar Genomic variation as it relates to human health
NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000021.4(PSEN1):c.737C>A (p.Ala246Glu)
Variation ID: 18125 Accession: VCV000018125.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.2 14: 73192832 (GRCh38) [ NCBI UCSC ] 14: 73659540 (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 Nov 24, 2024 Oct 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000021.4:c.737C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000012.1:p.Ala246Glu missense NM_007318.3:c.725C>A NP_015557.2:p.Ala242Glu missense NC_000014.9:g.73192832C>A NC_000014.8:g.73659540C>A NG_007386.2:g.61362C>A LRG_224:g.61362C>A LRG_224t1:c.737C>A LRG_224p1:p.Ala246Glu P49768:p.Ala246Glu - Protein change
- A246E, A242E
- Other names
- -
- Canonical SPDI
- NC_000014.9:73192831:C: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| PSEN1 | - | - |
GRCh38 GRCh37 |
529 | 546 | |
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 (3) |
criteria provided, single submitter
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Oct 9, 2024 | RCV000019753.30 | |
| Pathogenic (2) |
criteria provided, single submitter
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Aug 29, 2022 | RCV000084361.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2017 | RCV000542870.10 |
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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Pathogenic
(Aug 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002770445.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general … (more)
This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341). (less)
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Pathogenic
(Sep 11, 2017)
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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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000639608.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to … (more)
Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Alzheimer disease 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399926.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMIDs: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by two clinical laboratories (ClinVar) and has been reported in multiple individuals affected with familial Alzheimer disease (PMIDs: 7596406, 35847683, 33413468). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to elevate lysosomal pH in human fibroblasts, resulting in reduced protein autophagy and upregulated explression of genes and proteins linked to lysosomal pH (PMID: 24418614). In addition, transgenic mice models have shown elevated concentrations of A-beta protein in the absence of plaque formation, resulting in disinhibition, psychomotor slowing, and loss of motor skills (PMID: 12493631). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jun 29, 1995)
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no assertion criteria provided
Method: literature only
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ALZHEIMER DISEASE, FAMILIAL, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040051.2
First in ClinVar: Apr 04, 2013 Last updated: May 15, 2017 |
Comment on evidence:
In a pedigree with chromosome 14-linked early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in an … (more)
In a pedigree with chromosome 14-linked early-onset Alzheimer disease (AD3; 607822), Sherrington et al. (1995) identified a mutation in the PSEN1 gene, resulting in an ala246-to-glu substitution (A246E). (less)
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Likely pathogenic
(Jun 01, 2022)
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no assertion criteria provided
Method: provider interpretation
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Alzheimer disease 3
Affected status: yes
Allele origin:
inherited
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Solve-RD Consortium
Accession: SCV005091231.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
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Comment:
Variant confirmed as disease-causing by referring clinical team
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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: SCV000116497.1
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_29
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|
Comment:
Comment:
Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMIDs: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by two clinical laboratories (ClinVar) and has been reported in multiple individuals affected with familial Alzheimer disease (PMIDs: 7596406, 35847683, 33413468). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to elevate lysosomal pH in human fibroblasts, resulting in reduced protein autophagy and upregulated explression of genes and proteins linked to lysosomal pH (PMID: 24418614). In addition, transgenic mice models have shown elevated concentrations of A-beta protein in the absence of plaque formation, resulting in disinhibition, psychomotor slowing, and loss of motor skills (PMID: 12493631). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
This variant has been identified in multiple unrelated individuals with clinical features of Alzheimer disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. In vivo and in vitro studies showed this variant enhanced secretion of amyloid b protein-42 (Ab42) resulting in impairment (PMID: 10327206, 12493631, 25027006, 27930341).
Comment:
Experimental studies have shown that this missense change in human skin fibroblasts exhibits elevated lysosomal pH, reduced availability of active cathepsin D, reduces cleavage to the mature form of the enzyme, and also impairs degradation of autophagic substrates as compared to levels from control fibroblasts (PMID: 24418614). This variant also decreases rescuing activity in C. elegans (PMID: 9680315) and mice expressing the human A246E transgene show increased amyloid beta in the absence of plaques (PMID: 12493631). This variant has been reported to segregate with early onset Alzheimer’s disease (AD) in a single family (PMID: 7596406) and in individuals affected with early onset AD (PMID: 25174650, Invitae). ClinVar contains an entry for this variant (Variation ID: 18125). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glutamic acid at codon 246 of the PSEN1 protein (p.Ala246Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Alzheimer disease (PMIDs: 27930341, 28082723, 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated presenilin domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic by two clinical laboratories (ClinVar) and has been reported in multiple individuals affected with familial Alzheimer disease (PMIDs: 7596406, 35847683, 33413468). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The variant has been shown to elevate lysosomal pH in human fibroblasts, resulting in reduced protein autophagy and upregulated explression of genes and proteins linked to lysosomal pH (PMID: 24418614). In addition, transgenic mice models have shown elevated concentrations of A-beta protein in the absence of plaque formation, resulting in disinhibition, psychomotor slowing, and loss of motor skills (PMID: 12493631). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer's Disease Pathology, Constitute a Potential Object for Early Diagnosis. | Lopez-Toledo G | Frontiers in aging neuroscience | 2022 | PMID: 35847683 |
| Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro. | Raut S | Fluids and barriers of the CNS | 2021 | PMID: 33413468 |
| Generation and characterization of human induced pluripotent stem cell lines from a familial Alzheimer's disease PSEN1 A246E patient and a non-demented family member bearing wild-type PSEN1. | Muñoz SS | Stem cell research | 2018 | PMID: 30138848 |
| Dominant negative mechanism of Presenilin-1 mutations in FAD. | Watanabe H | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 29142009 |
| Presenilin-1 mutations and Alzheimer's disease. | Kelleher RJ 3rd | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28082723 |
| 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 |
| Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations. | Yang J | Oncotarget | 2017 | PMID: 27926491 |
| Loss of stability and hydrophobicity of presenilin 1 mutations causing Alzheimer's disease. | Somavarapu AK | Journal of neurochemistry | 2016 | PMID: 26756738 |
| Mutation analysis of patients with neurodegenerative disorders using NeuroX array. | Ghani M | Neurobiology of aging | 2015 | PMID: 25174650 |
| Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid β-peptides (Aβ) by γ-secretase to increase 42-to-40-residue Aβ. | Fernandez MA | The Journal of biological chemistry | 2014 | PMID: 25239621 |
| Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties. | Mahairaki V | Stem cells and development | 2014 | PMID: 25027006 |
| Lysosomal alkalization and dysfunction in human fibroblasts with the Alzheimer's disease-linked presenilin 1 A246E mutation can be reversed with cAMP. | Coffey EE | Neuroscience | 2014 | PMID: 24418614 |
| Dissociation between the processivity and total activity of γ-secretase: implications for the mechanism of Alzheimer's disease-causing presenilin mutations. | Quintero-Monzon O | Biochemistry | 2011 | PMID: 21919498 |
| Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling. | Veeraraghavalu K | The Journal of neuroscience : the official journal of the Society for Neuroscience | 2010 | PMID: 20484632 |
| Familial Alzheimer's disease mutations in presenilin 1 do not alter levels of the secreted amyloid-beta protein precursor generated by beta-secretase cleavage. | Zhang C | Current Alzheimer research | 2010 | PMID: 20205669 |
| Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. | Gliebus G | American journal of Alzheimer's disease and other dementias | 2009 | PMID: 19776335 |
| Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. | Nelson O | The Journal of clinical investigation | 2007 | PMID: 17431506 |
| Presenilin 1 mutations in Polish families with early-onset Alzheimer's disease. | Kowalska A | Folia neuropathologica | 2004 | PMID: 15119739 |
| Transgenic mice expressing the PS1-A246E mutation: effects on spatial learning, exploration, anxiety, and motor coordination. | Lalonde R | Behavioural brain research | 2003 | PMID: 12493631 |
| Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. | Murayama O | Neuroscience letters | 1999 | PMID: 10327206 |
| Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. | Baumeister R | Genes and function | 1997 | PMID: 9680315 |
| Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. | Sherrington R | Nature | 1995 | PMID: 7596406 |
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Text-mined citations for rs63750526 ...
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 Nov 25, 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.