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NM_000021.4(PSEN1):c.791C>T (p.Pro264Leu) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 24, 2023
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:
RCV001387954.7

Allele description [Variation Report for NM_000021.4(PSEN1):c.791C>T (p.Pro264Leu)]

NM_000021.4(PSEN1):c.791C>T (p.Pro264Leu)

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.791C>T (p.Pro264Leu)
HGVS:
  • NC_000014.9:g.73198052C>T
  • NG_007386.2:g.66582C>T
  • NM_000021.4:c.791C>TMANE SELECT
  • NM_007318.3:c.779C>T
  • NP_000012.1:p.Pro264Leu
  • NP_015557.2:p.Pro260Leu
  • LRG_224t1:c.791C>T
  • LRG_224:g.66582C>T
  • LRG_224p1:p.Pro264Leu
  • NC_000014.8:g.73664760C>T
  • NM_000021.3:c.791C>T
  • P49768:p.Pro264Leu
Protein change:
P260L
Links:
UniProtKB: P49768#VAR_006444; dbSNP: rs63750301
NCBI 1000 Genomes Browser:
rs63750301
Molecular consequence:
  • NM_000021.4:c.791C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007318.3:c.779C>T - 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
SCV001588727Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Aug 24, 2023) 		germlineclinical testing

PubMed (6)
[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

Mutations of the presenilin I gene in families with early-onset Alzheimer's disease.

Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S, et al.

Hum Mol Genet. 1995 Dec;4(12):2373-7.

PubMed [citation]
PMID:
8634712

Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update.

Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D.

J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20.

PubMed [citation]
PMID:
16033913
PMCID:
PMC1735922
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001588727.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This missense change has been observed in individuals with early-onset Alzheimer disease (PMID: 8634712, 16033913, 28350801). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs63750301, gnomAD 0.005%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 264 of the PSEN1 protein (p.Pro264Leu). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 11959395, 26438723). 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. ClinVar contains an entry for this variant (Variation ID: 98080).

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

Last Updated: Sep 1, 2024