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NM_001110.4(ADAM10):c.541A>G (p.Arg181Gly) AND Alzheimer disease 18

Germline classification:
risk factor (1 submission)
Last evaluated:
Oct 16, 2013
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000077798.3

Allele description [Variation Report for NM_001110.4(ADAM10):c.541A>G (p.Arg181Gly)]

NM_001110.4(ADAM10):c.541A>G (p.Arg181Gly)

Gene:
ADAM10:ADAM metallopeptidase domain 10 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.3
Genomic location:
Preferred name:
NM_001110.4(ADAM10):c.541A>G (p.Arg181Gly)
HGVS:
  • NC_000015.10:g.58665141T>C
  • NG_033876.1:g.89838A>G
  • NG_033876.2:g.89567A>G
  • NM_001110.4:c.541A>GMANE SELECT
  • NM_001320570.2:c.541A>G
  • NP_001101.1:p.Arg181Gly
  • NP_001307499.1:p.Arg181Gly
  • NC_000015.9:g.58957340T>C
  • O14672:p.Arg181Gly
Protein change:
R181G; ARG181GLY
Links:
UniProtKB: O14672#VAR_070909; OMIM: 602192.0007; dbSNP: rs145518263
NCBI 1000 Genomes Browser:
rs145518263
Molecular consequence:
  • NM_001110.4:c.541A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320570.2:c.541A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Alzheimer disease 18 (AD18)
Synonyms:
ALZHEIMER DISEASE 18, LATE-ONSET; ALZHEIMER DISEASE 18, SUSCEPTIBILITY TO
Identifiers:
MONDO: MONDO:0014265; MedGen: C3810041; OMIM: 615590

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000109632OMIM
no assertion criteria provided
risk factor
(Oct 16, 2013) 		germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity.

Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, Norton D, Tesco G, Elliott K, Wagner SL, Moir RD, Becker KD, Tanzi RE.

Hum Mol Genet. 2009 Oct 15;18(20):3987-96. doi: 10.1093/hmg/ddp323. Epub 2009 Jul 15.

PubMed [citation]
PMID:
19608551
PMCID:
PMC2748890

ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function.

Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE.

Neuron. 2013 Oct 16;80(2):385-401. doi: 10.1016/j.neuron.2013.08.035. Epub 2013 Sep 19.

PubMed [citation]
PMID:
24055016
PMCID:
PMC4105199

Details of each submission

From OMIM, SCV000109632.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In 4 affected individuals from 3 unrelated families with late-onset Alzheimer disease (AD18; 615590), Kim et al. (2009) identified a heterozygous mutation in the ADAM10 gene, resulting in an arg181-to-gly (R181G) substitution in the prodomain. The mutation was found by direct sequencing of the ADAM10 gene after genetic association was suggested by SNP analysis. The mutation did not segregate perfectly with the disorder: 2 patients with AD did not carry the mutation, and 2 unaffected family members did carry the mutation. These findings suggested either incomplete penetrance or the involvement of additional factors. In vitro functional studies showed that the mutation significantly attenuated alpha-secretase activity of ADAM10 (greater than 70% decrease) and elevated A-beta levels (1.5- to 3.5-fold).

Suh et al. (2013) confirmed the pathogenicity of the R181G mutation in transgenic mouse studies. The mutation attenuated alpha-secretase activity of ADAM10 and shifted APP processing toward beta-secretase-mediated cleavage, resulting in enhanced beta-amyloid plaque load and reactive gliosis.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 23, 2022