NM_000027.4(AGA):c.346C>T (p.Arg116Trp) AND Aspartylglucosaminuria

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Feb 18, 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:: RCV000049351.9

Allele description [Variation Report for NM_000027.4(AGA):c.346C>T (p.Arg116Trp)]

NM_000027.4(AGA):c.346C>T (p.Arg116Trp)

Gene:

AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q34.3

Genomic location:

Preferred name:

NM_000027.4(AGA):c.346C>T (p.Arg116Trp)

HGVS:

NC_000004.12:g.177439624G>A
NG_011845.2:g.7880C>T
NM_000027.4:c.346C>TMANE SELECT
NM_001171988.2:c.346C>T
NP_000018.2:p.Arg116Trp
NP_001165459.1:p.Arg116Trp
NC_000004.11:g.178360778G>A
NM_000027.3:c.346C>T
NR_033655.2:n.408C>T

Protein change:

R116W

Links:

dbSNP: rs386833423

NCBI 1000 Genomes Browser:

rs386833423

Molecular consequence:

NM_000027.4:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171988.2:c.346C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_033655.2:n.408C>T - 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
SCV000081783	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (1) [See all records that cite this PMID]
SCV001574483	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27876883, 23271757, 28492532
SCV002104010	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27876883, 33439067, 23271757 Citation Link,
SCV004217772	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 18, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000081783

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
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria.

Banning A, Gülec C, Rouvinen J, Gray SJ, Tikkanen R.

Sci Rep. 2016 Nov 23;6:37583. doi: 10.1038/srep37583.

PubMed [citation]

PMID:: 27876883
PMCID:: PMC5120323

See all PubMed Citations (5)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000081783.1

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

Description

Converted during submission to Likely pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574483.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects AGA function (PMID: 27876883). 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 not expected to disrupt AGA protein function. ClinVar contains an entry for this variant (Variation ID: 55942). This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 23271757). This variant is present in population databases (rs386833423, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 116 of the AGA protein (p.Arg116Trp).

#	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, SCV002104010.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: AGA c.346C>T (p.Arg116Trp) 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 4e-06 in 251442 control chromosomes. c.346C>T has been reported in the literature as a homozygous genotype in three siblings from at-least one consanguineous Turkish family affected with Aspartylglucosaminuria and has been cited by others (example, Opaladen_2014 and Goodspeed_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal activity in leukocytes, fibroblasts and in-vitro (example, Opaladen_2014, Banning_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. 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 Baylor Genetics, SCV004217772.2

#	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: Oct 8, 2024

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