NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Oct 29, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000172586.19

Allele description [Variation Report for NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg)]

NM_000447.3(PSEN2):c.208G>A (p.Gly70Arg)

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.208G>A (p.Gly70Arg)

HGVS:

NC_000001.11:g.226883771G>A
NG_007381.2:g.18588G>A
NM_000447.3:c.208G>AMANE SELECT
NM_012486.3:c.208G>A
NP_000438.2:p.Gly70Arg
NP_036618.2:p.Gly70Arg
LRG_225t1:c.208G>A
LRG_225:g.18588G>A
LRG_225p1:p.Gly70Arg
NC_000001.10:g.227071472G>A
NG_007381.1:g.18200G>A
NM_000447.2:c.208G>A

Protein change:

G70R

Links:

dbSNP: rs139972151

NCBI 1000 Genomes Browser:

rs139972151

Molecular consequence:

NM_000447.3:c.208G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_012486.3:c.208G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000051047	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	Likely benign (Jun 24, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001550278	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV002049340	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Oct 29, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000051047

Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq

criteria provided, single submitter

(Ng et al. (Circ Cardiovasc Genet. 2013))

Likely benign
(Jun 24, 2013)

unknown

research

PubMed (1)
[See all records that cite this PMID]

SCV001550278

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV002049340

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Oct 29, 2021)

germline

clinical testing

Citation Link

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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	2	not provided	not provided	not provided	not provided	research

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000051047.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550278.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002049340.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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

#	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: Nov 3, 2024

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