rs104894595

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000263.4(NAGLU):c.1562C>T(p.Pro521Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,612,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P521P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:1O:1

Conservation

PhyloP100: 7.60

Publications

15 publications found

Variant links:

Genes affected

NAGLU (HGNC:7632): (N-acetyl-alpha-glucosaminidase) This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. [provided by RefSeq, Jul 2008]

NAGLU Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 3B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, Myriad Women’s Health
Charcot-Marie-Tooth disease axonal type 2V
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

NAGLU links:

ENSG00000266929 (HGNC:):

ENSG00000266929 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000263.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-42543568-C-T is Pathogenic according to our data. Variant chr17-42543568-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGLU	NM_000263.4 link	c.1562C>T	p.Pro521Leu	missense_variant	Exon 6 of 6	ENST00000225927.7	NP_000254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NAGLU	ENST00000225927.7 link	c.1562C>T	p.Pro521Leu	missense_variant	Exon 6 of 6	1	NM_000263.4	ENSP00000225927.1
NAGLU	ENST00000591587.1 link	c.*531C>T		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000467836.1
ENSG00000266929	ENST00000585572.1 link	n.379+4813C>T		intron_variant	Intron 3 of 4	4
NAGLU	ENST00000592454.1 link	c.*405C>T		downstream_gene_variant		2		ENSP00000468665.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

245890

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000452

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000699

AC:

102

AN:

1460016

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726304

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.000101

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000836

AC:

AN:

1111796

Other (OTH)

AF:

0.0000663

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000468

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Pathogenic:5Uncertain:1

Aug 25, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

Feb 13, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NAGLU c.1562C>T (p.Pro521Leu) results in a non-conservative amino acid change located in the C-terminal 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 2.6e-05 in 271726 control chromosomes (gnomAD). c.1562C>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (e.g. Zhao 1998, Beesley 2005, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:curation

Feb 08, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The NAGLU c.1562C>T (p.Pro521Leu) variant has been reported in 13 individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) and is reported to segregate with disease in nine individuals in two families (Beesley CE et al., PMID: 9832037; Valstar MJ et al., PMID: 20852935; Weber B et al., PMID: 10094189; Zhao HG et al., PMID: 9443875; Zheng Q et al., PMID: 28306536). Of those individuals, nine were compound heterozygous for the variant and a pathogenic/likely pathogenic variant was confirmed to be in trans (Valstar MJ et al., PMID: 20852935; Zhao HG et al., PMID: 9443875) and two individuals were homozygous for the variant (Beesley CE et al., PMID: 9832037; Weber B et al., PMID: 10094189). This variant is only observed on 7 out of 277,290 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to NAGLU function. This variant has been reported in the ClinVar database as a pathogenic or likely pathogenic germline variant by seven submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

not provided

Pathogenic:3

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 02, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V

Pathogenic:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 521 of the NAGLU protein (p.Pro521Leu). This variant is present in population databases (rs104894595, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9443875, 20852935, 28306536). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1566). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mucopolysaccharidosis

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.7

PhyloP100

7.6

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Vest4

0.95

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.92

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over