NM_000027.4(AGA):c.367_371del (p.Thr123fs) AND Aspartylglucosaminuria

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 29, 2023
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:: RCV001060563.12

Allele description [Variation Report for NM_000027.4(AGA):c.367_371del (p.Thr123fs)]

NM_000027.4(AGA):c.367_371del (p.Thr123fs)

Gene:

AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

4q34.3

Genomic location:

Preferred name:

NM_000027.4(AGA):c.367_371del (p.Thr123fs)

HGVS:

NC_000004.12:g.177439602_177439606del
NG_011845.2:g.7901_7905del
NM_000027.4:c.367_371delMANE SELECT
NM_001171988.2:c.367_371del
NP_000018.2:p.Thr123fs
NP_001165459.1:p.Thr123fs
NC_000004.11:g.178360753_178360757del
NC_000004.11:g.178360756_178360760del
NM_000027.3:c.367_371del
NM_000027.4:c.367_371delACACAMANE SELECT
NR_033655.2:n.429_433del

Protein change:

T123fs

Links:

dbSNP: rs1736928101

NCBI 1000 Genomes Browser:

rs1736928101

Molecular consequence:

NM_000027.4:c.367_371del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001171988.2:c.367_371del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_033655.2:n.429_433del - 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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ACA79131 (0)
MeSH
Arabidopsis thaliana RING/U-box superfamily protein (AT1G04360), mRNA
Arabidopsis thaliana RING/U-box superfamily protein (AT1G04360), mRNA
gi|1063680154|ref|NM_100316.3|

Nucleotide
Homo sapiens 5'-aminolevulinate synthase 1 (ALAS1), transcript variant 1, mRNA; ...
Homo sapiens 5'-aminolevulinate synthase 1 (ALAS1), transcript variant 1, mRNA; nuclear gene for mitochondrial product
gi|1519246506|ref|NM_000688.6|

Nucleotide
Thouarella variabilis isolate F6 28S ribosomal RNA gene, partial sequence
Thouarella variabilis isolate F6 28S ribosomal RNA gene, partial sequence
gi|747037601|gb|KP324580.1|

Nucleotide
Ophionotus victoriae
Ophionotus victoriae
Ophionotus victoriae RefSeq Genome

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001225262	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7627186, 11309371, 8457202, 28492532
SCV001573055	Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2019)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060047	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 16, 2021)	unknown	clinical testing	Citation Link,
SCV004217582	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 29, 2023)	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	paternal	yes	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

Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene.

Isoniemi A, Hietala M, Aula P, Jalanko A, Peltonen L.

Hum Mutat. 1995;5(4):318-26.

PubMed [citation]

PMID:: 7627186

Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations.

Saarela J, Laine M, Oinonen C, von Schantz C, Jalanko A, Rouvinen J, Peltonen L.

Hum Mol Genet. 2001 Apr 15;10(9):983-95.

PubMed [citation]

PMID:: 11309371

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225262.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in AGA are known to be pathogenic (PMID: 7627186, 11309371). This variant has been observed in an individual affected with aspartylglucosaminuria (PMID: 8457202). This variant is also known as a 5 bp deletion (ACACA) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr123Hisfs*20) in the AGA gene. It is expected to result in an absent or disrupted protein product.

#	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 Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS, SCV001573055.1

#	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	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060047.2

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

Description

NM_000027.3(AGA):c.367_371del5(T123Hfs*20) is a frameshifting truncation variant classified as likely pathogenic in the context of aspartylglucosaminuria. T123Hfs*20 has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. T123Hfs*20 has not been observed in population frequency databases. In summary, NM_000027.3(AGA):c.367_371del5(T123Hfs*20) is a frameshifting truncation variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. 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 Baylor Genetics, SCV004217582.1

#	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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