This variant is interpreted as a Likely Benign, for Alzheimer disease 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:15663477). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1-Supporting => BS1 downgraded in strength to supporting.
ClinVar Genomic variation as it relates to human health
NM_000447.3(PSEN2):c.185G>A (p.Arg62His)
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.
(14)
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.
Benign/Likely benign
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000447.3(PSEN2):c.185G>A (p.Arg62His)
Variation ID: 97995 Accession: VCV000097995.33
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q42.13 1: 226883748 (GRCh38) [ NCBI UCSC ] 1: 227071449 (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 Oct 20, 2024 Jan 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000447.3:c.185G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000438.2:p.Arg62His missense NM_012486.3:c.185G>A NP_036618.2:p.Arg62His missense NC_000001.11:g.226883748G>A NC_000001.10:g.227071449G>A NG_007381.2:g.18565G>A LRG_225:g.18565G>A LRG_225t1:c.185G>A LRG_225p1:p.Arg62His P49810:p.Arg62His - Protein change
- R62H
- Other names
-
NM_000447.2(PSEN2):c.185G>A(p.Arg62His)
NM_012486.2(PSEN2):c.185G>A(p.Arg62His)
- Canonical SPDI
- NC_000001.11:226883747: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.
-
0.01797 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00861
Exome Aggregation Consortium (ExAC) 0.00990
Trans-Omics for Precision Medicine (TOPMed) 0.01365
The Genome Aggregation Database (gnomAD) 0.01433
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01438
1000 Genomes Project 30x 0.01733
1000 Genomes Project 0.01797
- 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. |
|||
| PSEN2 | - | - |
GRCh38 GRCh37 |
283 | 326 | |
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. |
|---|---|---|---|---|
| Benign (1) |
criteria provided, single submitter
|
Jun 24, 2013 | RCV000172777.5 | |
| Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 22, 2023 | RCV000084258.20 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000283560.7 | |
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 23, 2024 | RCV000641029.16 | |
| Benign (4) |
criteria provided, single submitter
|
Apr 24, 2021 | RCV001664396.7 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Alzheimer disease
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051595.2 First in ClinVar: Jun 04, 2015 Last updated: Sep 14, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. HGMD phenotype assertion is uncertain. Pathogenicity categories were based on literature … (more)
The study set was not selected for affection status in relation to any cancer. HGMD phenotype assertion is uncertain. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
|
Number of individuals with the variant: 3
|
|
|
Benign
(Apr 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001880008.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005263807.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
|
Likely benign
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Alzheimer disease 4
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803616.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
Comment:
This variant is interpreted as a Likely Benign, for Alzheimer disease 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS3 => Well-established … (more)
This variant is interpreted as a Likely Benign, for Alzheimer disease 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:15663477). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1-Supporting => BS1 downgraded in strength to supporting. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease 4
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000355166.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1V
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000355165.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Benign
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease 4
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000762647.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Sep 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564748.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004009940.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
PSEN2: BP4, BS1, BS2
Number of individuals with the variant: 1
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924517.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930481.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809664.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965073.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
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: SCV000116394.1
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_50
|
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
PSEN2: BP4, BS1, BS2
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 is interpreted as a Likely Benign, for Alzheimer disease 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:15663477). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1-Supporting => BS1 downgraded in strength to supporting.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
PSEN2: BP4, BS1, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Investigating APOE, APP-Aβ metabolism genes and Alzheimer's disease GWAS hits in brain small vessel ischemic disease. | Blumenau S | Scientific reports | 2020 | PMID: 32345996 |
| Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. | Hsu S | Neurobiology of disease | 2020 | PMID: 32087291 |
| PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. | Jia L | Alzheimer's & dementia : the journal of the Alzheimer's Association | 2020 | PMID: 31914229 |
| Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. | Koriath C | Molecular psychiatry | 2020 | PMID: 30279455 |
| Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease. | Ryan NS | Neurobiology of aging | 2015 | PMID: 26410308 |
| Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy. | Ferrari R | Current Alzheimer research | 2015 | PMID: 26159191 |
| On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. | Sala Frigerio C | Alzheimer's & dementia : the journal of the Alzheimer's Association | 2015 | PMID: 25937274 |
| Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. | Schulte EC | European journal of human genetics : EJHG | 2015 | PMID: 25604855 |
| Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. | Sassi C | Neurobiology of aging | 2014 | PMID: 25104557 |
| The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE-ε4 carriers. | Benitez BA | PLoS genetics | 2013 | PMID: 23990795 |
| C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. | Wojtas A | American journal of neurodegenerative disease | 2012 | PMID: 23383383 |
| 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 |
| Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. | Cruchaga C | PloS one | 2012 | PMID: 22312439 |
| Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort. | Dobricic V | Neurobiology of aging | 2012 | PMID: 22221884 |
| Presenilin-2 gene mutation presenting as Lewy body dementia? | Raciti L | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2011 | PMID: 21409510 |
| Protein aggregates and novel presenilin gene variants in idiopathic dilated cardiomyopathy. | Gianni D | Circulation | 2010 | PMID: 20194882 |
| Novel MAPT Val75Ala mutation and PSEN2 Arg62Hys in two siblings with frontotemporal dementia. | Gallo M | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2010 | PMID: 19768372 |
| Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. | Guerreiro RJ | Neurobiology of aging | 2010 | PMID: 18667258 |
| Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. | Ertekin-Taner N | Neurology | 2008 | PMID: 17914065 |
| Functional characterization of novel presenilin-2 variants identified in human breast cancers. | To MD | Oncogene | 2006 | PMID: 16474849 |
| Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. | Walker ES | Journal of neurochemistry | 2005 | PMID: 15663477 |
| Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. | Sleegers K | Brain : a journal of neurology | 2004 | PMID: 15130954 |
| Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. | Cruts M | Human molecular genetics | 1998 | PMID: 9384602 |
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Text-mined citations for rs58973334 ...
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.