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.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 5
- First in ClinVar:
- Feb 20, 2014
- Most recent Submission:
- Feb 7, 2023
- Last evaluated:
- Aug 27, 2021
- Accession:
- VCV000098015.8
- Variation ID:
- 98015
- Description:
- single nucleotide variant
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NM_000021.4(PSEN1):c.344A>G (p.Tyr115Cys)
- Allele ID
- 103907
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 14q24.2
- Genomic location
- 14: 73173571 (GRCh38) GRCh38 UCSC
- 14: 73640279 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000021.4:c.344A>G MANE Select NP_000012.1:p.Tyr115Cys missense NM_007318.3:c.332A>G NP_015557.2:p.Tyr111Cys missense NC_000014.9:g.73173571A>G NC_000014.8:g.73640279A>G NG_007386.2:g.42101A>G LRG_224:g.42101A>G LRG_224t1:c.344A>G LRG_224p1:p.Tyr115Cys P49768:p.Tyr115Cys - Protein change
- Y115C, Y111C
- Other names
- -
- Canonical SPDI
- NC_000014.9:73173570:A:G
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA225002
- UniProtKB: P49768#VAR_006416
- dbSNP: rs63750450
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Likely pathogenic | 2 | criteria provided, multiple submitters, no conflicts | May 21, 2020 | RCV001199924.2 | |
| Pathogenic | 2 | criteria provided, single submitter | Nov 13, 2015 | RCV000084295.2 | |
| Pathogenic | 1 | criteria provided, single submitter | Aug 27, 2021 | RCV000640610.5 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Nov 13, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics Inc
Accession: SCV000843414.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 |
|
|
|
Likely pathogenic
(May 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease, type 3
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370703.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease 3
Pick disease Acne inversa, familial, 3 Frontotemporal dementia
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000762204.3
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces tyrosine with cysteine at codon 115 of the PSEN1 protein (p.Tyr115Cys). The tyrosine residue is highly conserved and there is a … (more)
This sequence change replaces tyrosine with cysteine at codon 115 of the PSEN1 protein (p.Tyr115Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with early onset Alzheimer disease (PMID: 9384602, 27777022, 28350801). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98015). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 25921538). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Alzheimer disease 3
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001425405.1
First in ClinVar: Aug 01, 2020 Last updated: Aug 01, 2020 |
|
|
|
not provided
(-)
|
no assertion provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
VIB Department of Molecular Genetics, University of Antwerp
Accession: SCV000116431.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_7
|
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease. | Hung COY | Cell reports | 2018 | PMID: 30590039 |
| APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. | Lanoiselée HM | PLoS medicine | 2017 | PMID: 28350801 |
| Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. | Ryan NS | The Lancet. Neurology | 2016 | PMID: 27777022 |
| APP metabolism regulates tau proteostasis in human cerebral cortex neurons. | Moore S | Cell reports | 2015 | PMID: 25921538 |
| Subjects harboring presenilin familial Alzheimer's disease mutations exhibit diverse white matter biochemistry alterations. | Roher AE | American journal of neurodegenerative disease | 2013 | PMID: 24093083 |
| Abstracts of the Sixteenth Meeting of the European Neurological Society. May 27-31, 2006. Lausanne, Switzerland. | - | Journal of neurology | 2006 | PMID: 16710641 |
| Early onset familial Alzheimer's disease: Mutation frequency in 31 families. | Janssen JC | Neurology | 2003 | PMID: 12552037 |
| Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. | Rogaeva EA | Neurology | 2001 | PMID: 11524469 |
| Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. | De Jonghe C | Human molecular genetics | 1999 | PMID: 10401002 |
| Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. | Cruts M | Human molecular genetics | 1998 | PMID: 9384602 |
| A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21. | van Duijn CM | American journal of human genetics | 1994 | PMID: 7942850 |
Text-mined citations for rs63750450...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Feb 07, 2023