NM_000021.4(PSEN1):c.832A>G (p.Arg278Gly) AND Alzheimer disease 3

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 22, 2024
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:: RCV003320398.3

Allele description [Variation Report for NM_000021.4(PSEN1):c.832A>G (p.Arg278Gly)]

NM_000021.4(PSEN1):c.832A>G (p.Arg278Gly)

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.832A>G (p.Arg278Gly)

HGVS:

NC_000014.9:g.73198093A>G
NG_007386.2:g.66623A>G
NM_000021.4:c.832A>GMANE SELECT
NM_007318.3:c.820A>G
NP_000012.1:p.Arg278Gly
NP_015557.2:p.Arg274Gly
LRG_224t1:c.832A>G
LRG_224:g.66623A>G
LRG_224p1:p.Arg278Gly
NC_000014.8:g.73664801A>G

Protein change:

R274G

Molecular consequence:

NM_000021.4:c.832A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007318.3:c.820A>G - 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

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soma ferritin-like [Limulus polyphemus]
soma ferritin-like [Limulus polyphemus]
gi|926608421|ref|XP_013777907.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003930350	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2024)	germline	research	PubMed (2) [See all records that cite these PMIDs] 37712079, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003930350

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2024)

germline

research

PubMed (2)
[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	yes	1	1	not provided	not provided	not provided	research

Citations

PubMed

The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.

Mahungu AC, Steyn E, Floudiotis N, Wilson LA, Vandrovcova J, Reilly MM, Record CJ, Benatar M, Wu G, Raga S, Wilmshurst JM, Naidu K, Hanna M, Nel M, Heckmann JM.

Front Neurol. 2023;14:1239725. doi: 10.3389/fneur.2023.1239725.

PubMed [citation]

PMID:: 37712079
PMCID:: PMC10497947

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Neurogenomics Lab, Neuroscience Institute, University Of Cape Town, SCV003930350.2

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

Description

PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PP3_strong: REVEL score is 0.98. PM1 not met: pathogenic variants appear to be distributed throughout the gene. PM5 met: PSEN1 p.Arg278Ile and p.Arg278Thr classified as pathogenic. Sequencing funded by the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium: https://create.rarediseasesnetwork.org.

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

Last Updated: Jun 2, 2024

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