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NM_000021.4(PSEN1):c.811C>G (p.Leu271Val) AND Alzheimer disease 3

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 22, 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:
RCV002051789.2

Allele description [Variation Report for NM_000021.4(PSEN1):c.811C>G (p.Leu271Val)]

NM_000021.4(PSEN1):c.811C>G (p.Leu271Val)

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.811C>G (p.Leu271Val)
HGVS:
  • NC_000014.9:g.73198072C>G
  • NG_007386.2:g.66602C>G
  • NM_000021.4:c.811C>GMANE SELECT
  • NM_007318.3:c.799C>G
  • NP_000012.1:p.Leu271Val
  • NP_015557.2:p.Leu267Val
  • LRG_224t1:c.811C>G
  • LRG_224:g.66602C>G
  • LRG_224p1:p.Leu271Val
  • NC_000014.8:g.73664780C>G
  • NM_000021.3:c.811C>G
  • P49768:p.Leu271Val
Protein change:
L267V; LEU271VAL
Links:
UniProtKB: P49768#VAR_016220; OMIM: 104311.0026; dbSNP: rs63750886
NCBI 1000 Genomes Browser:
rs63750886
Molecular consequence:
  • NM_000021.4:c.811C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_007318.3:c.799C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV0023185373billion
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 22, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing

Citations

PubMed

Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy.

Kwok JB, Halliday GM, Brooks WS, Dolios G, Laudon H, Murayama O, Hallupp M, Badenhop RF, Vickers J, Wang R, Naslund J, Takashima A, Gandy SE, Schofield PR.

J Biol Chem. 2003 Feb 28;278(9):6748-54. Epub 2002 Dec 19.

PubMed [citation]
PMID:
12493737

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From 3billion, SCV002318537.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PSEN1 related disorder (ClinVar ID: VCV000018148, PMID:12493737). The variant was co-segregated with Alzheimer disease, type 3, with spastic paraparesis and unusual plaques in multiple affected family members (PMID: 12493737). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12493737). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94>=0.6, 3CNET: 0.883>=0.75). A missense variant is a common mechanism . It is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 7, 2023