NM_000021.4(PSEN1):c.344A>G (p.Tyr115Cys) AND Alzheimer disease 3

Clinical significance:Likely pathogenic (Last evaluated: May 21, 2020)
Review status:2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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Based on:: 2 submissions [Details]
Record status:: current
Accession:: RCV001199924.2

Allele description [Variation Report for NM_000021.4(PSEN1):c.344A>G (p.Tyr115Cys)]

NM_000021.4(PSEN1):c.344A>G (p.Tyr115Cys)

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.344A>G (p.Tyr115Cys)

HGVS:

NC_000014.9:g.73173571A>G
NG_007386.2:g.42101A>G
NM_000021.4:c.344A>GMANE SELECT
NM_007318.3:c.332A>G
NP_000012.1:p.Tyr115Cys
NP_015557.2:p.Tyr111Cys
LRG_224t1:c.344A>G
LRG_224:g.42101A>G
LRG_224p1:p.Tyr115Cys
NC_000014.8:g.73640279A>G
NM_000021.3:c.344A>G
P49768:p.Tyr115Cys

Protein change:

Y111C

Links:

UniProtKB: P49768#VAR_006416; dbSNP: rs63750450

NCBI 1000 Genomes Browser:

rs63750450

Molecular consequence:

NM_000021.4:c.344A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007318.3:c.332A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Alzheimer disease 3
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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001370703	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter LabCorp Variant Classification Summary - May 2015	Likely pathogenic (May 5, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9384602, 30590039, 28350801, 25921538, 27777022 Citation Link,
SCV001425405	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter ACMG Guidelines, 2015	Likely pathogenic (May 21, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25921538, 27777022, 28350801, 30590039, 9384602, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001370703

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

LabCorp Variant Classification Summary - May 2015

Likely pathogenic
(May 5, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001425405

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

ACMG Guidelines, 2015

Likely pathogenic
(May 21, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

Help

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

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ.

Cell Rep. 2015 May 5;11(5):689-96. doi: 10.1016/j.celrep.2015.03.068. Epub 2015 Apr 23.

PubMed [citation]

PMID:: 25921538
PMCID:: PMC4431668

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.

Ryan NS, Nicholas JM, Weston PSJ, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC.

Lancet Neurol. 2016 Dec;15(13):1326-1335. doi: 10.1016/S1474-4422(16)30193-4. Epub 2016 Oct 21.

PubMed [citation]

PMID:: 27777022

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370703.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: PSEN1 c.344A>G (p.Tyr115Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD). c.344A>G has been reported in the literature in multiple individuals and families affected with Alzheimer Disease (e.g. Cruts_1998, Ryan_2016, Lanoiselee_2017). These data indicate that the variant is very likely to be associated with disease. Publications reporting experimental evidence show the variant alters protein function, and results in major defects in lysosome function and autophagy in human neurons (Moore_2015, Hung_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425405.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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: Feb 7, 2023

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