NM_000027.4(AGA):c.488G>C (p.Cys163Ser) AND Aspartylglucosaminuria

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 21, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000410114.19

Allele description [Variation Report for NM_000027.4(AGA):c.488G>C (p.Cys163Ser)]

NM_000027.4(AGA):c.488G>C (p.Cys163Ser)

Gene:

AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q34.3

Genomic location:

Preferred name:

NM_000027.4(AGA):c.488G>C (p.Cys163Ser)

HGVS:

NC_000004.12:g.177438764C>G
NG_011845.2:g.8740G>C
NM_000027.4:c.488G>CMANE SELECT
NM_001171988.2:c.488G>C
NP_000018.2:p.Cys163Ser
NP_001165459.1:p.Cys163Ser
NC_000004.11:g.178359918C>G
NM_000027.3:c.488G>C
NR_033655.2:n.550G>C
P20933:p.Cys163Ser

Protein change:

C163S; CYS163SER

Links:

UniProtKB: P20933#VAR_005073; OMIM: 613228.0001; dbSNP: rs121964904

NCBI 1000 Genomes Browser:

rs121964904

Molecular consequence:

NM_000027.4:c.488G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001171988.2:c.488G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_033655.2:n.550G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Aspartylglucosaminuria (AGU)
Synonyms:: GLYCOASPARAGINASE; Aspartylglycosaminuria; Aspartylglucos-aminuria; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008830; MedGen: C0268225; Orphanet: 93; OMIM: 208400; Human Phenotype Ontology: HP:0012068

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001142339	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Likely pathogenic (Jan 6, 2020)	germline	curation
SCV001193819	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 19, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11309371, 1904874, 1559710, 1765378, 9742145 Citation Link,
SCV001207113	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 20, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1765378, 8172656, 1703489, 1904874, 2011603, 7627186, 11309371, 21228398, 28492532
SCV001467838	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 16, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1904874, 1703489, 9742145, 11309371, 8172656, 8064811, 27876883 Citation Link,
SCV002084886	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 14, 2020)	germline	clinical testing
SCV002810975	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004217638	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Convenient and quantitative determination of the frequency of a mutant allele using solid-phase minisequencing: application to aspartylglucosaminuria in Finland.

Syvänen AC, Ikonen E, Manninen T, Bengtström M, Söderlund H, Aula P, Peltonen L.

Genomics. 1992 Mar;12(3):590-5.

PubMed [citation]

PMID:: 1559710

In vitro mutagenesis helps to unravel the biological consequences of aspartylglucosaminuria mutation.

Ikonen E, Enomaa N, Ulmanen I, Peltonen L.

Genomics. 1991 Sep;11(1):206-11.

PubMed [citation]

PMID:: 1765378

See all PubMed Citations (14)

Details of each submission

From Reproductive Health Research and Development, BGI Genomics, SCV001142339.1

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

Description

NM_000027.3:c.488G>C in the AGA gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The c.488G>C (p.Cys163Ser) variant has been reported previously in the compound heterozygous states (C163S/R161Q) in association with aspartylglucosaminuria (PMID: 1904874; 7627186; 2011603). In vitro functional studies demonstrated that p.Cys163Ser results in deficient enzyme activity (PMID: 1904874; 1765378). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3; PS3; PP4.

#	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

From Myriad Genetics, Inc., SCV001193819.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_000027.3(AGA):c.488G>C(C163S) is classified as pathogenic in the context of aspartylglucosaminuria. Sources cited for classification include the following: PMID 11309371, 1904874, 1559710, 1765378 and 9742145. Classification of NM_000027.3(AGA):c.488G>C(C163S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207113.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant is also known as AGAFin. ClinVar contains an entry for this variant (Variation ID: 219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AGA protein function. Experimental studies have shown that this missense change affects AGA function (PMID: 1765378, 1904874, 8172656). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 1703489, 1904874, 2011603, 7627186, 11309371, 21228398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 163 of the AGA protein (p.Cys163Ser). This variant is present in population databases (rs121964904, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467838.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: AGA c.488G>C (p.Cys163Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251288 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488G>C has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Aspartylglucosaminuria (Fisher_1991, Ikonen_1991, Tollersrud_1994, Saarela_2001). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant impaired processing of the precursor molecule into subunits and reduced AGA activity (Fish_1991, Riikonen_1994, Banning_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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

From Natera, Inc., SCV002084886.1

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

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002810975.1

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

From Baylor Genetics, SCV004217638.2

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

Last Updated: Sep 29, 2024

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