NM_000027.4(AGA):c.770C>T (p.Thr257Ile) AND Aspartylglucosaminuria

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000049362.6

Allele description [Variation Report for NM_000027.4(AGA):c.770C>T (p.Thr257Ile)]

NM_000027.4(AGA):c.770C>T (p.Thr257Ile)

Gene:

AGA:aspartylglucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q34.3

Genomic location:

Preferred name:

NM_000027.4(AGA):c.770C>T (p.Thr257Ile)

HGVS:

NC_000004.12:g.177434418G>A
NG_011845.2:g.13086C>T
NM_000027.4:c.770C>TMANE SELECT
NM_001171988.2:c.740C>T
NP_000018.2:p.Thr257Ile
NP_001165459.1:p.Thr247Ile
NC_000004.11:g.178355572G>A
NM_000027.3:c.770C>T
NR_033655.2:n.756C>T
P20933:p.Thr257Ile

Protein change:

T247I

Links:

UniProtKB: P20933#VAR_015432; dbSNP: rs386833434

NCBI 1000 Genomes Browser:

rs386833434

Molecular consequence:

NM_000027.4:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001171988.2:c.740C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_033655.2:n.756C>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
SCV000081794	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]
SCV003525620	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29993127, 11309371, 28492532
SCV004217649	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 21, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000081794

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

no assertion criteria provided

probable-pathogenic

not provided

PubMed (1)
[See all records that cite this PMID]

SCV003525620

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 23, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004217649

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 21, 2023)

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: SCV000081794

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

Biochemical and structural insights into an allelic variant causing the lysosomal storage disorder - aspartylglucosaminuria.

Pande S, Bizilj W, Guo HC.

FEBS Lett. 2018 Aug;592(15):2550-2561. doi: 10.1002/1873-3468.13190. Epub 2018 Jul 23.

PubMed [citation]

PMID:: 29993127
PMCID:: PMC6119092

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 (4)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000081794.1

#	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, SCV003525620.2

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 257 of the AGA protein (p.Thr257Ile). This variant is present in population databases (rs386833434, gnomAD 0.004%). 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. Experimental studies have shown that this missense change affects AGA function (PMID: 11309371, 29993127). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 55953). This variant is also known as Thr234Ile. This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 11309371).

#	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, SCV004217649.1

#	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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