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NM_000021.4(PSEN1):c.869-2A>G AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 21, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003783617.1

Allele description

NM_000021.4(PSEN1):c.869-2A>G

Gene:
PSEN1:presenilin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q24.2
Genomic location:
Preferred name:
NM_000021.4(PSEN1):c.869-2A>G
HGVS:
  • NC_000014.9:g.73206384A>G
  • NG_007386.2:g.74914A>G
  • NM_000021.4:c.869-2A>GMANE SELECT
  • NM_007318.3:c.857-2A>G
  • LRG_224t1:c.869-2A>G
  • LRG_224:g.74914A>G
  • NC_000014.8:g.73673092A>G
Molecular consequence:
  • NM_000021.4:c.869-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_007318.3:c.857-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:
Alzheimer disease 3 (AD3)
Synonyms:
Alzheimer disease early onset type 3; ALZHEIMER DISEASE, FAMILIAL, 3
Identifiers:
MONDO: MONDO:0011913; MedGen: C1843013; Orphanet: 1020; OMIM: 607822
Name:
Frontotemporal dementia (FTD1)
Synonyms:
FRONTOTEMPORAL LOBE DEMENTIA; WILHELMSEN-LYNCH DISEASE; Dementia, frontotemporal, with parkinsonism; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0017276; MedGen: C0338451; Orphanet: 282; OMIM: 600274; Human Phenotype Ontology: HP:0002145
Name:
Pick disease
Synonyms:
PICK DISEASE OF BRAIN; LOBAR ATROPHY OF BRAIN; Pick's disease; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008243; MedGen: C0236642; Orphanet: 282; OMIM: 172700
Name:
Acne inversa, familial, 3 (ACNINV3)
Identifiers:
MONDO: MONDO:0013398; MedGen: C3151038; OMIM: 613737

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004570891Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 21, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease.

Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MN, Pottier C, Breusegem SY, Mathur PP, Jenardhanan P, Le Guennec K, Mukadam AS, Quenez O, Coutant S, Rousseau S, Richard AC, Boland A, Deleuze JF, Frebourg T, Hannequin D, Campion D; CNR-MAJ collaborators..

Mol Psychiatry. 2015 Sep;20(9):1046-56. doi: 10.1038/mp.2015.100. Epub 2015 Jul 21.

PubMed [citation]
PMID:
26194182

The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects.

Blauwendraat C, Wilke C, Simón-Sánchez J, Jansen IE, Reifschneider A, Capell A, Haass C, Castillo-Lizardo M, Biskup S, Maetzler W, Rizzu P, Heutink P, Synofzik M.

Genet Med. 2018 Feb;20(2):240-249. doi: 10.1038/gim.2017.102. Epub 2017 Jul 27.

PubMed [citation]
PMID:
28749476
PMCID:
PMC5846812
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV004570891.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Disruption of this splice site has been observed in individual(s) with clinical features of PSEN1-related conditions (PMID: 26194182, 28749476, 32579498). In at least one individual the variant was observed to be de novo. 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. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PSEN1 cause disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 1, 2024