NM_000027.3(AGA):c.488G>C (p.Cys163Ser)

NM_000027.3(AGA):c.488G>C (p.Cys163Ser)

Variant type:
single nucleotide variant
Cytogenetic location:
4q34
Genomic location:
  • Chr4:177438764 (on Assembly GRCh38)
  • Chr4:178359918 (on Assembly GRCh37)
Protein change:
C163S
HGVS:
  • NG_011845.2:g.8740G>C
  • NM_000027.3:c.488G>C
  • NR_033655.1:n.616G>C
  • NC_000004.12:g.177438764C>G
  • NC_000004.11:g.178359918C>G
  • NP_000018.2:p.Cys163Ser
Links:
NCBI 1000 Genomes Browser:
rs121964904
Molecular consequence:
  • NM_000027.3:c.488G>C: missense variant SO:0001583
  • NR_033655.1:n.616G>C: non-coding transcript variant SO:0001619
Allele frequency:
GMAF 0.00090 (G)

Clinical significance

NM_000027.3(AGA):c.488G>C (p.Cys163Ser)

Clinical significance:
Pathogenic/Likely pathogenic
Review status:
(1/4)1 star out of maximum of 4 stars
classified by single submitter
Number of submission(s):
1
Condition(s)
  • Aspartylglucosaminuria, finnish type[MedGen]
See supporting ClinVar records

Recent Activity

Assertion and evidence details

Germline

Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter
(Last submitted)
Submission accession
Pathogenic
(Jan 28, 2010)
classified by single submitter
(literature only)
literature only
  • Aspartylglucosaminuria, finnish type[MedGen]
germlinePubMed (6)
OMIM
(Dec 30, 2010)
SCV000020387

Summary

FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided

OMIM

Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline

Description

By direct sequencing of PCR-amplified AGA cDNA from an AGU patient (208400), Ikonen et al. (1991) found a G-to-C mutation resulting in the substitution of serine for cysteine-163 (C163S). This mutation was found in all of 20 analyzed Finnish AGU patients, and in heterozygous form in all 53 carriers, and in none of 67 control individuals. The mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge.
Fisher et al. (1991) independently found the G-to-C transversion in DNA from Finnish AGU fibroblasts; however, they found a second G-to-A transition that resulted in an arginine-to-glutamine substitution as well. The 2 substitutions were present in all 3 Finnish cases studied and in none of 2 non-Finnish AGU fibroblast lines. In non-Finnish AGU fibroblasts, Fisher et al. (1991) found deletions as the apparent cause of the AGA deficiency. Mononen et al. (1991) likewise found 2 mutations, R161Q and C163S. Both mutations resulted in novel restriction endonuclease sites and were present in all 8 Finnish AGU patients studied, but they were absent from Finnish and non-Finnish controls and a non-Finnish case of AGU. Both amino acid changes would be expected to modify the structure of the protein profoundly: the replacement of an arginine by glutamine represents the substitution of a basic amino acid for one containing an uncharged polar group; the replacement of cysteine by serine may abolish a disulfide bridge. Whether both mutations are involved in the pathologic consequences or whether one mutation is a polymorphism was uncertain.
Ikonen et al. (1991) showed by in vitro mutagenesis studies that the cys163-to-ser mutation is responsible for enzyme deficiency, whereas the arg161-to-gln substitution, which accompanies the other mutation in 98% of AGU alleles in Finland, represents a rare polymorphism. Cysteine-163 was shown to participate in an S-S bridge. The absence of this covalent crosslink in the mutated protein probably results in disturbed folding of the polypeptide chain and consequent decrease in its intracellular stability. Fisher and Aronson (1991) likewise found the 482G-A transition and the 488G-C transversion and demonstrated that only the latter was responsible for deficiency of glycosylasparaginase activity. The substitution prevented the normal posttranslational processing of the precursor polypeptide into its alpha and beta subunits.
The C163S mutation is responsible for 98% of the cases of AGU in Finland (Isoniemi et al., 1995).

Last Updated: Aug 5, 2014

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