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NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 21, 2021
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:
RCV001949489.6

Allele description [Variation Report for NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys)]

NM_000021.4(PSEN1):c.838G>A (p.Glu280Lys)

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.838G>A (p.Glu280Lys)
HGVS:
  • NC_000014.9:g.73198099G>A
  • NG_007386.2:g.66629G>A
  • NM_000021.4:c.838G>AMANE SELECT
  • NM_007318.3:c.826G>A
  • NP_000012.1:p.Glu280Lys
  • NP_015557.2:p.Glu276Lys
  • LRG_224t1:c.838G>A
  • LRG_224:g.66629G>A
  • LRG_224p1:p.Glu280Lys
  • NC_000014.8:g.73664807G>A
Protein change:
E276K
Links:
dbSNP: rs2140105309
NCBI 1000 Genomes Browser:
rs2140105309
Molecular consequence:
  • NM_000021.4:c.838G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007318.3:c.826G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002238301Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 21, 2021) 		germlineclinical testing

PubMed (9)
[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

The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.

Alzheimer's Disease Collaborative Group..

Nat Genet. 1995 Oct;11(2):219-22.

PubMed [citation]
PMID:
7550356

Familial Alzheimer disease presenilin-1 mutations alter the active site conformation of γ-secretase.

Chau DM, Crump CJ, Villa JC, Scheinberg DA, Li YM.

J Biol Chem. 2012 May 18;287(21):17288-17296. doi: 10.1074/jbc.M111.300483. Epub 2012 Mar 29.

PubMed [citation]
PMID:
22461631
PMCID:
PMC3366784
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV002238301.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu280 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7550356, 22461631, 22766738, 24217025, 25471389, 27930341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with Alzheimer disease (PMID: 26396515, 33188256). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 280 of the PSEN1 protein (p.Glu280Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.

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

Last Updated: Sep 1, 2024