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rs421016

From SNPedia

Orientationplus
Stabilizedplus
Geno Mag Summary
(A;A) 0 normal/common
(A;G) 3 5x higher risk for Parkinson's; Carrier of Gaucher disease allele
(G;G) 6 Gaucher disease; at least 5x higher risk of Parkinson's
ReferenceGRCh38 38.1/141
Chromosome1
Position155205043
GeneGBA
is asnp
is mentioned by
dbSNPrs421016
ebirs421016
HLIrs421016
Exacrs421016
Varsomers421016
Maprs421016
PheGenIrs421016
hapmaprs421016
1000 genomesrs421016
hgdprs421016
ensemblrs421016
gopubmedrs421016
geneviewrs421016
scholarrs421016
googlers421016
pharmgkbrs421016
gwascentralrs421016
openSNPrs421016
23andMers421016
23andMe allrs421016
SNP Nexus

SNPshotrs421016
SNPdbers421016
MSV3drs421016
GWAS Ctlgrs421016
Merged fromRs35095275
Max Magnitude6

rs421016, also known as L444P or Leu444Pro, is a SNP causing an amino acid change in the GBA gene; it is among the most common mutations associated with Gaucher disease of any type. [PMID 3353383OA-icon.png] Amino acid predictions from genome sequence may predict this as L483P or Leu483Pro; this disparity in position calling may be due to a 39 peptide signal sequence. Polyphen 2 predicts P04062 L483P to be "possibly damaging" with a score of 0.857 (sensitivity: 0.83; specificity: 0.93). (P04062 is the uniprot ID for GBA.)

The risk allele (in current dbSNP orientation) is (G), and as the inheritance is autosomal recessive, individuals must either be compound heterozygotes (for two different GBA mutations) or rs421016(G;G) homozygotes to develop Gaucher disease. There are over 300 mutations now known to occur in the GBA gene, with many associated with increasing risk for either type I, II, or III Gaucher disease.

This SNP (along with others associated with Gaucher disease) is studied extensively in Ashkenazi Jewish populations where it is found in relatively high frequency.

Note: this SNP used to have a "mirror" SNP, rs35095275, representing the opposite strand yet the same exact nucleotide position; it has now been merged into this SNP.

One copy of rs421016(G) has also been shown to increase the risk of Parkinson's disease ~5 fold across multiple ethnicities, and to lower a bit the age of onset of Parkinson's.[PMID 19846850OA-icon.png] In one study, the estimated age-specific risk for Parkinson's disease at 60 and 80 years of age was 4.7% and 9.1% among Gaucher disease patients, i.e. those carrying two Gaucher GBA mutations, compared with 1.5% and 7.7% among GBA mutation heterozygotes, and 0.7% and 2.1% for carriers of zero Gaucher GBA mutations, respectively. Note that these risks are pooled over multiple GBA mutations including rs421016 as well as other GBA variants.[PMID 24756352OA-icon.png]

OMIM606463
Desc
Variant0001
Relatedalso
OMIM606463
Desc
Variant0009
Relatedalso


ClinVar
Risk rs421016(C,G;C,G)
Alt rs421016(C,G;C,G)
Reference rs421016(A;A)
Significance Other
Disease Acute neuronopathic Gaucher's disease Subacute neuronopathic Gaucher's disease Gaucher's disease Parkinson disease Dementia Gaucher disease Gaucher disease
Variation info
Gene GBA
CLNDBN Acute neuronopathic Gaucher's disease Subacute neuronopathic Gaucher's disease Gaucher's disease, type 1 Parkinson disease, late-onset Dementia, Lewy body, susceptibility to Gaucher disease, perinatal lethal Gaucher disease
Reversed 0
HGVS NC_000001.10:g.155205043A>G
CLNSRC HGMD OMIM Allelic Variant
CLNACC RCV000004509.8, RCV000004510.9, RCV000004511.8, RCV000004512.7, RCV000004513.7, RCV000004533.4, RCV000004534.4, RCV000004535.4, RCV000004536.4, RCV000020150.1, RCV000225393.1, RCV000225500.1,



[PMID 2309702OA-icon.png] Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene.

[PMID 2349952OA-icon.png] Complex alleles of the acid beta-glucosidase gene in Gaucher disease.

[PMID 2464926OA-icon.png] Characterization of mutations in Gaucher patients by cDNA cloning.

[PMID 2880291] A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease.