VCV000599622.6 - ClinVar

NM_000021.4(PSEN1):c.869-1G>A

Germline

Classification

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.

(4)

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/Likely pathogenic

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.869-1G>A

Variation ID: 599622 Accession: VCV000599622.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.2 14: 73206385 (GRCh38) [ NCBI UCSC ] 14: 73673093 (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	Jan 22, 2019	Feb 28, 2024	Mar 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000021.4:c.869-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_007318.3:c.857-1G>A		splice acceptor
NC_000014.9:g.73206385G>A
NC_000014.8:g.73673093G>A
NG_007386.2:g.74915G>A
LRG_224:g.74915G>A
LRG_224t1:c.869-1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000014.9:73206384:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

dbSNP: rs63750219 VarSome

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
Gene	OMIM	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.
Alzheimer disease	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2017	RCV000736261.2
Alzheimer disease 3	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 21, 2023	RCV002470967.4
Acne inversa, familial, 3 Alzheimer disease 3 Frontotemporal dementia Pick disease	Pathogenic (1)	criteria provided, single submitter	Aug 10, 2022	RCV002533770.4

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.
Likely pathogenic (Feb 01, 2017)	criteria provided, single submitter (Koriath et al. 2018) Method: research	Alzheimer disease type 1 Affected status: yes Allele origin: inherited	Human Genetics Group at Institute of Prion Diseases London, University College London Accession: SCV000864558.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 Comment: Confirmed by Sanger sequencing	Publications: PubMed (1) PubMed: 30279455 Comment: CADD score 26.7, not on exac, intronic mutation. Human Splice Finder predicts a broken WT site and Alteration of the WT acceptor site, most probably … (more) CADD score 26.7, not on exac, intronic mutation. Human Splice Finder predicts a broken WT site and Alteration of the WT acceptor site, most probably affecting splicing. (less) Number of individuals with the variant: 1
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alzheimer disease 3 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767443.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (10) PubMed: 9452052‚ 10075646‚ 11198283‚ 12615638‚ 26194182‚ 27777022‚ 28350801‚ 28749476‚ 29142009‚ 30279455 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 PSEN1-related disease (PMID: 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been functionally proven to result in exon 9 skipping, and the formation of a cysteine residue at position 290 (p.Ser290_Ser319delinsCys). Furthermore, it was has been demonstrated that the missense variant, rather than the exon deletion, is responsible for causing protein misfunction (PMID: 9452052, PMID: 10075646). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant affects the annotated cleavage site (UniProt). (I) 0703 - Other canonical splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants (c.869-1G>T, c.869-2A>T), have been reported as pathogenic and de novo, or observed in a family with Alzheimer’s disease (ClinVar, LOVD, PMID: 27777022). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. There are multiple alternative genomic changes reported (c.869-2A>G, exon 9 deletion) that have been functional proven to result in the same protein outcome (p.Ser290_Ser319delinsCys). This variant has been reported in multiple families with Alzheimer’s disease, dementia and/or spastic paraparesis (ClinVar, LOVD, PMID: 9452052, PMID: 30279455, PMID: 26194182, PMID: 28350801, PMID: 28749476, PMID: 11198283). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to result in defects in proteolytic processing, resulting in accumulation of uncleaved protein (PMID: 10075646). (SP) 1205 - This variant has been shown to be maternally inherited by a peer-reviewed study, where this individual's family was assessed (EOFAD-2; PMID: 12615638). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Aug 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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: SCV003442341.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 9452052‚ 12615638‚ 30090657 Comment: For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 9, … (more) For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 9452052, 12615638). ClinVar contains an entry for this variant (Variation ID: 599622). This variant is also known as c.857-1G>A or AG > AA substitution at the acceptor site of intron 9 . Disruption of this splice site has been observed in individuals with Alzheimer disease (PMID: 9452052, 12615638, 30090657). 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 affects an acceptor splice site in intron 8 of the PSEN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. (less)
Pathogenic (Mar 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Alzheimer disease 3 Affected status: yes Allele origin: germline	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University Accession: SCV003932784.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 30090657 Comment: This case has this variant as heterozygous Number of individuals with the variant: 1 Age: 40-49 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Anatolian Peninsula

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 PSEN1-related disease (PMID: 29142009). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been functionally proven to result in exon 9 skipping, and the formation of a cysteine residue at position 290 (p.Ser290_Ser319delinsCys). Furthermore, it was has been demonstrated that the missense variant, rather than the exon deletion, is responsible for causing protein misfunction (PMID: 9452052, PMID: 10075646). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant affects the annotated cleavage site (UniProt). (I) 0703 - Other canonical splice variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants (c.869-1G>T, c.869-2A>T), have been reported as pathogenic and de novo, or observed in a family with Alzheimer’s disease (ClinVar, LOVD, PMID: 27777022). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. There are multiple alternative genomic changes reported (c.869-2A>G, exon 9 deletion) that have been functional proven to result in the same protein outcome (p.Ser290_Ser319delinsCys). This variant has been reported in multiple families with Alzheimer’s disease, dementia and/or spastic paraparesis (ClinVar, LOVD, PMID: 9452052, PMID: 30279455, PMID: 26194182, PMID: 28350801, PMID: 28749476, PMID: 11198283). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to result in defects in proteolytic processing, resulting in accumulation of uncleaved protein (PMID: 10075646). (SP) 1205 - This variant has been shown to be maternally inherited by a peer-reviewed study, where this individual's family was assessed (EOFAD-2; PMID: 12615638). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 9452052, 12615638). ClinVar contains an entry for this variant (Variation ID: 599622). This variant is also known as c.857-1G>A or AG > AA substitution at the acceptor site of intron 9 . Disruption of this splice site has been observed in individuals with Alzheimer disease (PMID: 9452052, 12615638, 30090657). 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 affects an acceptor splice site in intron 8 of the PSEN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia.	Xu Y	Aging and disease	2018	PMID: 30090657
The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects.	Blauwendraat C	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28749476
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
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
Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.	Ryan NS	The Lancet. Neurology	2016	PMID: 27777022
De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.	Rovelet-Lecrux A	Molecular psychiatry	2015	PMID: 26194182
Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions.	Brooks WS	Brain : a journal of neurology	2003	PMID: 12615638
Variable phenotype of Alzheimer's disease with spastic paraparesis.	Smith MJ	Annals of neurology	2001	PMID: 11198283
The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing.	Steiner H	The Journal of biological chemistry	1999	PMID: 10075646
Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease.	Sato S	Human mutation	1998	PMID: 9452052
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Text-mined citations for rs63750219 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000021.4(PSEN1):c.869-1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750219 ...