NM_000027.4(AGA):c.376C>G (p.Leu126Val) AND Aspartylglucosaminuria

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Nov 1, 2022
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:: RCV000805244.10

Allele description [Variation Report for NM_000027.4(AGA):c.376C>G (p.Leu126Val)]

NM_000027.4(AGA):c.376C>G (p.Leu126Val)

Gene:

AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q34.3

Genomic location:

Preferred name:

NM_000027.4(AGA):c.376C>G (p.Leu126Val)

HGVS:

NC_000004.12:g.177439594G>C
NG_011845.2:g.7910C>G
NM_000027.4:c.376C>GMANE SELECT
NM_001171988.2:c.376C>G
NP_000018.2:p.Leu126Val
NP_001165459.1:p.Leu126Val
NC_000004.11:g.178360748G>C
NM_000027.3:c.376C>G
NR_033655.2:n.438C>G

Protein change:

L126V

Links:

dbSNP: rs200420067

NCBI 1000 Genomes Browser:

rs200420067

Molecular consequence:

NM_000027.4:c.376C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001171988.2:c.376C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_033655.2:n.438C>G - 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
SCV000945192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001306084	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1722323, 18992224, 9737998, 25456816, 11309371 Citation Link,
SCV001461150	Natera, Inc.	no assertion criteria provided	Uncertain significance (Apr 16, 2020)	germline	clinical testing
SCV002797084	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 7, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	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

Spectrum of mutations in aspartylglucosaminuria.

Ikonen E, Aula P, Grön K, Tollersrud O, Halila R, Manninen T, Syvänen AC, Peltonen L.

Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11222-6.

PubMed [citation]

PMID:: 1722323
PMCID:: PMC53106

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000945192.2

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 126 of the AGA protein (p.Leu126Val). This variant is present in population databases (rs200420067, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AGA-related conditions. ClinVar contains an entry for this variant (Variation ID: 650146). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Illumina Laboratory Services, Illumina, SCV001306084.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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., SCV001461150.1

#	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, SCV002797084.1

#	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

Last Updated: Sep 29, 2024

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