NM_000447.3(PSEN2):c.712C>T (p.Leu238Phe) AND Alzheimer disease 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 12, 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:: RCV001857923.11

Allele description [Variation Report for NM_000447.3(PSEN2):c.712C>T (p.Leu238Phe)]

NM_000447.3(PSEN2):c.712C>T (p.Leu238Phe)

Gene:

PSEN2:presenilin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q42.13

Genomic location:

Preferred name:

NM_000447.3(PSEN2):c.712C>T (p.Leu238Phe)

HGVS:

NC_000001.11:g.226888974C>T
NG_007381.2:g.23791C>T
NM_000447.3:c.712C>TMANE SELECT
NM_012486.3:c.712C>T
NP_000438.2:p.Leu238Phe
NP_036618.2:p.Leu238Phe
LRG_225t1:c.712C>T
LRG_225:g.23791C>T
LRG_225p1:p.Leu238Phe
NC_000001.10:g.227076675C>T
NG_007381.1:g.23403C>T
NM_000447.2:c.712C>T

Protein change:

L238F

Links:

dbSNP: rs367855127

NCBI 1000 Genomes Browser:

rs367855127

Molecular consequence:

NM_000447.3:c.712C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012486.3:c.712C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Alzheimer disease 4 (AD4)
Synonyms:: Alzheimer disease familial type 4
Identifiers:: MONDO: MONDO:0011743; MedGen: C1847200; Orphanet: 1020; OMIM: 606889

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002178071	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25937274, 30021643, 32087291, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002178071

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients.

Sala Frigerio C, Lau P, Troakes C, Deramecourt V, Gele P, Van Loo P, Voet T, De Strooper B.

Alzheimers Dement. 2015 Nov;11(11):1265-76. doi: 10.1016/j.jalz.2015.02.007. Epub 2015 Apr 29.

PubMed [citation]

PMID:: 25937274

Discovery and validation of autosomal dominant Alzheimer's disease mutations.

Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TLS, Goate AM, Cruchaga C, Bateman RJ; Dominantly Inherited Alzheimer Network (DIAN)., Karch CM.

Alzheimers Res Ther. 2018 Jul 18;10(1):67. doi: 10.1186/s13195-018-0392-9.

PubMed [citation]

PMID:: 30021643
PMCID:: PMC6052673

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002178071.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 238 of the PSEN2 protein (p.Leu238Phe). This variant is present in population databases (rs367855127, gnomAD 0.004%). This missense change has been observed in individual(s) with Alzheimer's disease (PMID: 25937274, 30021643). ClinVar contains an entry for this variant (Variation ID: 448151). 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 PSEN2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PSEN2 function (PMID: 30021643, 32087291). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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