NM_000263.4(NAGLU):c.1772T>C (p.Leu591Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 8, 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:: RCV001855608.6

Allele description [Variation Report for NM_000263.4(NAGLU):c.1772T>C (p.Leu591Pro)]

NM_000263.4(NAGLU):c.1772T>C (p.Leu591Pro)

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.1772T>C (p.Leu591Pro)

HGVS:

NC_000017.11:g.42543778T>C
NG_011552.1:g.12846T>C
NM_000263.4:c.1772T>CMANE SELECT
NP_000254.2:p.Leu591Pro
NC_000017.10:g.40695796T>C
NM_000263.3:c.1772T>C

Protein change:

L591P

Links:

dbSNP: rs1215582852

NCBI 1000 Genomes Browser:

rs1215582852

Molecular consequence:

NM_000263.4:c.1772T>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002116927	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9832037, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002116927

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (2)
[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

Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB).

Beesley CE, Young EP, Vellodi A, Winchester BG.

J Med Genet. 1998 Nov;35(11):910-4.

PubMed [citation]

PMID:: 9832037
PMCID:: PMC1051483

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002116927.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 591 of the NAGLU protein (p.Leu591Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type IIIB (PMID: 9832037; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558175). 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 with a positive predictive value of 95%. For these reasons, this variant has been 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

Last Updated: Oct 26, 2024

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