NM_000263.4(NAGLU):c.1675G>T (p.Asp559Tyr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003781491.2

Allele description [Variation Report for NM_000263.4(NAGLU):c.1675G>T (p.Asp559Tyr)]

NM_000263.4(NAGLU):c.1675G>T (p.Asp559Tyr)

Gene:

NAGLU:N-acetyl-alpha-glucosaminidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_000263.4(NAGLU):c.1675G>T (p.Asp559Tyr)

HGVS:

NC_000017.11:g.42543681G>T
NG_011552.1:g.12749G>T
NM_000263.4:c.1675G>TMANE SELECT
NP_000254.2:p.Asp559Tyr
NC_000017.10:g.40695699G>T

Protein change:

D559Y

Molecular consequence:

NM_000263.4:c.1675G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-III-B (MPS3B)
Synonyms:: NAGLU DEFICIENCY; Mucopoly-saccharidosis type 3B; Sanfilippo syndrome B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009656; MedGen: C0086648; OMIM: 252920

Name:: Charcot-Marie-Tooth disease axonal type 2V
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2V; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2V
Identifiers:: MONDO: MONDO:0014665; MedGen: C5569050; Orphanet: 447964; OMIM: 616491

Recent activity

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protein aim19 [Schizosaccharomyces pombe]
protein aim19 [Schizosaccharomyces pombe]
gi|19112376|ref|NP_595584.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004573357	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32447333, 28018442, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004573357

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 15, 2023)

germline

clinical testing

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

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

Citations

PubMed

Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients.

Kong W, Meng Y, Zou L, Yang G, Wang J, Shi X.

J Pediatr Endocrinol Metab. 2020 May 24;33(6):793-802. doi: 10.1515/jpem-2019-0505.

PubMed [citation]

PMID:: 32447333

Long-term clinical course of a patient with mucopolysaccharidosis type IIIB.

Kim JH, Chi YH, Kim GH, Yoo HW, Lee JH.

Korean J Pediatr. 2016 Nov;59(Suppl 1):S37-S40. doi: 10.3345/kjp.2016.59.11.S37. Epub 2016 Nov 30.

PubMed [citation]

PMID:: 28018442
PMCID:: PMC5177708

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004573357.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp559 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been observed in individuals with NAGLU-related conditions (PMID: 32447333), which suggests that this may be a clinically significant amino acid residue. 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 NAGLU protein function. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 28018442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 559 of the NAGLU protein (p.Asp559Tyr).

#	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

Last Updated: Sep 29, 2024

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