ClinVar Genomic variation as it relates to human health
NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(3); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg)
Variation ID: 192129 Accession: VCV000192129.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q42.13 1: 226883771 (GRCh38) [ NCBI UCSC ] 1: 227071472 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 8, 2015 Mar 16, 2024 Dec 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000447.3:c.208G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000438.2:p.Gly70Arg missense NM_012486.3:c.208G>A NP_036618.2:p.Gly70Arg missense NC_000001.11:g.226883771G>A NC_000001.10:g.227071472G>A NG_007381.2:g.18588G>A LRG_225:g.18588G>A LRG_225t1:c.208G>A LRG_225p1:p.Gly70Arg - Protein change
- G70R
- Other names
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- Canonical SPDI
- NC_000001.11:226883770:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PSEN2 | - | - |
GRCh38 GRCh37 |
279 | 322 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 29, 2021 | RCV000172586.19 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 26, 2021 | RCV001852098.14 | |
PSEN2-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV003416064.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Jun 24, 2013)
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criteria provided, single submitter
Method: research
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Not provided
Affected status: unknown
Allele origin:
unknown
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000051047.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
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Number of individuals with the variant: 2
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Uncertain significance
(Oct 29, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049340.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The PSEN2 c.208G>A; p.Gly70Arg variant (rs139972151) has been described in at least two individuals who had a clinical diagnosis of Alzheimer’s disease, but no additional … (more)
The PSEN2 c.208G>A; p.Gly70Arg variant (rs139972151) has been described in at least two individuals who had a clinical diagnosis of Alzheimer’s disease, but no additional clinical information was available (Wojtas 2012, see link to Alzheimer’s Association International Conference (AAIC) 2019 abstract). This variant contains an entry in ClinVar (Variation ID: 192129), and is found in the non-Finnish European population with an allele frequency of 0.011% (14/129028 alleles) in the Genome Aggregation Database. The glycine at codon 70 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.456). However, given the lack of clinical and functional data, the significance of the p.Gly70Arg variant is uncertain at this time. REFERENCES Wojtas A et al. C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis. 2012;1(1):107-18. PMID: 23383383. Link to AAIC 2019 P3-120 abstract: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2019.06.3148 (less)
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Uncertain significance
(Mar 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alzheimer disease 4
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002154653.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Alzheimer disease (PMID: 23383383). ClinVar contains an entry for this variant (Variation ID: 192129). This variant is present in population databases (rs139972151, ExAC 0.009%). This sequence change replaces glycine with arginine at codon 70 of the PSEN2 protein (p.Gly70Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. (less)
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Uncertain significance
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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PSEN2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115735.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The PSEN2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Arg. This variant was reported in a patient with early-onset Alzheimer's disease … (more)
The PSEN2 c.208G>A variant is predicted to result in the amino acid substitution p.Gly70Arg. This variant was reported in a patient with early-onset Alzheimer's disease (Wojtas et al. 2012. PubMed ID: 23383383) and as a likely benign variant in a study of patients with coronary artery disease risk (Ng et al. 2013. PubMed ID: 23861362). It is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550278.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PSEN2 p.Gly70Arg variant was identified in 1 of 454 proband chromosomes (frequency: 0.0022) from a cohort of 227 unrelated probands clinically diagnosed for Alzheimer … (more)
The PSEN2 p.Gly70Arg variant was identified in 1 of 454 proband chromosomes (frequency: 0.0022) from a cohort of 227 unrelated probands clinically diagnosed for Alzheimer disease with symptoms occuring before 70 years old (Wojtas_2012_PMID:23383383). The variant was identified in dbSNP (ID: rs139972151) and ClinVar (classified as likely benign by Biesecker Lab). The variant was identified in control databases in 17 of 282688 chromosomes at a frequency of 0.00006014 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 14 of 129028 chromosomes (freq: 0.000109), Latino in 2 of 35436 chromosomes (freq: 0.000056) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Gly70 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. | Wojtas A | American journal of neurodegenerative disease | 2012 | PMID: 23383383 |
Text-mined citations for rs139972151 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.