NM_000447.3(PSEN2):c.205C>G (p.Pro69Ala) AND Alzheimer disease 4

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 10, 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:: RCV002516567.6

Allele description [Variation Report for NM_000447.3(PSEN2):c.205C>G (p.Pro69Ala)]

NM_000447.3(PSEN2):c.205C>G (p.Pro69Ala)

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.205C>G (p.Pro69Ala)

HGVS:

NC_000001.11:g.226883768C>G
NG_007381.2:g.18585C>G
NM_000447.3:c.205C>GMANE SELECT
NM_012486.3:c.205C>G
NP_000438.2:p.Pro69Ala
NP_036618.2:p.Pro69Ala
LRG_225t1:c.205C>G
LRG_225:g.18585C>G
LRG_225p1:p.Pro69Ala
NC_000001.10:g.227071469C>G
NG_007381.1:g.18197C>G
NM_000447.2:c.205C>G

Protein change:

P69A

Links:

dbSNP: rs202133351

NCBI 1000 Genomes Browser:

rs202133351

Molecular consequence:

NM_000447.3:c.205C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_012486.3:c.205C>G - 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
SCV003472834	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22221884, 32087291, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003472834

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 10, 2023)

germline

clinical testing

PubMed (3)
[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

Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort.

Dobricic V, Stefanova E, Jankovic M, Gurunlian N, Novakovic I, Hardy J, Kostic V, Guerreiro R.

Neurobiol Aging. 2012 Jul;33(7):1481.e7-12. doi: 10.1016/j.neurobiolaging.2011.12.007. Epub 2012 Jan 4.

PubMed [citation]

PMID:: 22221884

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2.

Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM.

Neurobiol Dis. 2020 Jun;139:104817. doi: 10.1016/j.nbd.2020.104817. Epub 2020 Feb 19.

PubMed [citation]

PMID:: 32087291
PMCID:: PMC7236786

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003472834.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 69 of the PSEN2 protein (p.Pro69Ala). This variant is present in population databases (rs202133351, gnomAD 0.02%). This missense change has been observed in individual(s) with Alzheimer disease (PMID: 22221884). ClinVar contains an entry for this variant (Variation ID: 191771). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect PSEN2 function (PMID: 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: Oct 8, 2024

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