NM_000263.4(NAGLU):c.419A>G (p.Tyr140Cys) AND Mucopolysaccharidosis, MPS-III-B

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV000409594.9

Allele description [Variation Report for NM_000263.4(NAGLU):c.419A>G (p.Tyr140Cys)]

NM_000263.4(NAGLU):c.419A>G (p.Tyr140Cys)

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.419A>G (p.Tyr140Cys)

HGVS:

NC_000017.11:g.42537433A>G
NG_011552.1:g.6501A>G
NM_000263.4:c.419A>GMANE SELECT
NP_000254.2:p.Tyr140Cys
NC_000017.10:g.40689451A>G
NM_000263.3:c.419A>G

Protein change:

Y140C

Links:

dbSNP: rs753520553

NCBI 1000 Genomes Browser:

rs753520553

Molecular consequence:

NM_000263.4:c.419A>G - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487266	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Nov 4, 2016)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14984474, 9443875, 9832037, 9950362, 11153910, 9443878 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000919842	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 6, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9950362, 9832037, 11153910 Citation Link,
SCV000929906	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 9443875, 9443878, 25741868, 30809705
SCV001463380	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004041066	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051874	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
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

Sanfilippo B syndrome: molecular defects in Greek patients.

Beesley C, Moraitou M, Winchester B, Schulpis K, Dimitriou E, Michelakakis H.

Clin Genet. 2004 Feb;65(2):143-9.

PubMed [citation]

PMID:: 14984474

Mucopolysaccharidosis type IIIB (Sanfilippo B): identification of 18 novel alpha-N-acetylglucosaminidase gene mutations.

Bunge S, Knigge A, Steglich C, Kleijer WJ, van Diggelen OP, Beck M, Gal A.

J Med Genet. 1999 Jan;36(1):28-31.

PubMed [citation]

PMID:: 9950362
PMCID:: PMC1762943

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000487266.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919842.1

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

Description

Variant summary: NAGLU c.419A>G (p.Tyr140Cys) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246256 control chromosomes (gnomAD). The variant, c.419A>G, has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(Beesley_1998, Bunge_1998, Meijer_2016, Tessitore_2000). These data indicate that the variant is very likely to be associated with disease. The affected patients were found to have significantly decreased enzyme activity (<10%)(Beesley_1998). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was 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

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV000929906.1

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

Description

PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAC

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001463380.1

#	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 Baylor Genetics, SCV004041066.1

#	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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051874.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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