NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 22, 2017
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:: RCV000640605.7

Allele description [Variation Report for NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr)]

NM_000021.4(PSEN1):c.1229G>A (p.Cys410Tyr)

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.1229G>A (p.Cys410Tyr)

HGVS:

NC_000014.9:g.73217225G>A
NG_007386.2:g.85755G>A
NM_000021.4:c.1229G>AMANE SELECT
NM_007318.3:c.1217G>A
NP_000012.1:p.Cys410Tyr
NP_015557.2:p.Cys406Tyr
LRG_224t1:c.1229G>A
LRG_224:g.85755G>A
LRG_224p1:p.Cys410Tyr
NC_000014.8:g.73683933G>A
NM_000021.3:c.1229G>A
P49768:p.Cys410Tyr

Protein change:

C406Y; CYS410TYR

Links:

UniProtKB: P49768#VAR_006458; OMIM: 104311.0005; dbSNP: rs661

NCBI 1000 Genomes Browser:

rs661

Molecular consequence:

NM_000021.4:c.1229G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_007318.3:c.1217G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000762199	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2017)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 27100199, 24011544, 27100200, 23843529, 20484632, 27930341, 25741723, 22115042, 9680315, 17288597, 21559374, 9196071, 17545141, 17553989, 24880964, 7596406, 8634712, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000762199

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2017)

germline

clinical testing

PubMed (18)
[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

Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds.

Veugelen S, Saito T, Saido TC, Chávez-Gutiérrez L, De Strooper B.

Neuron. 2016 Apr 20;90(2):410-6. doi: 10.1016/j.neuron.2016.03.010.

PubMed [citation]

PMID:: 27100199

Familial Alzheimer's disease coding mutations reduce Presenilin-1 expression in a novel genomic locus reporter model.

Ahmadi S, Wade-Martins R.

Neurobiol Aging. 2014 Feb;35(2):443.e5-443.e16. doi: 10.1016/j.neurobiolaging.2013.07.026. Epub 2013 Sep 4.

PubMed [citation]

PMID:: 24011544

See all PubMed Citations (18)

Details of each submission

From Invitae, SCV000762199.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects protein function (PMID: 27100199, 24011544, 27100200, 23843529, 20484632, 27930341, 25741723, 22115042, 9680315, 17288597, 21559374, 9196071). This variant has been reported in families affected with early onset Alzheimer's disease (PMID: 17545141, 17553989, 24880964). This variant has also been to found segregate with early onset Alzheimer's disease in several families (PMID: 7596406, 8634712). ClinVar contains an entry for this variant (Variation ID: 18127). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 410 of the PSEN1 protein (p.Cys410Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.

#	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: Sep 1, 2024

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