chr17-42538691-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000263.4(NAGLU):c.700C>T(p.Arg234Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,892 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.88

Publications

14 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 16 ACMG points.

PM1

In a helix (size 19) in uniprot entity ANAG_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000263.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-42538691-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1013390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17-42538691-C-T is Pathogenic according to our data. Variant chr17-42538691-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1572.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.700C>T	p.Arg234Cys	missense_variant	Exon 4 of 6	ENST00000225927.7	NP_000254.2	P54802A0A140VJE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAGLU	ENST00000225927.7 link	c.700C>T	p.Arg234Cys	missense_variant	Exon 4 of 6	1	NM_000263.4	ENSP00000225927.1	P54802
NAGLU	ENST00000586516.5 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 3 of 4	2		ENSP00000467135.1	K7ENX5
NAGLU	ENST00000591587.1 link	c.295C>T	p.Arg99Cys	missense_variant	Exon 3 of 4	5		ENSP00000467836.1	K7EQH9
ENSG00000266929	ENST00000585572.1 link	n.315C>T		non_coding_transcript_exon_variant	Exon 3 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250926

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Pathogenic:5

Mar 25, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.700C>T;p.(Arg234Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 1572; PMID: 9832037; PMID: 30070758; PMID: 11286389; PMID: 18218046; PMID: 23380547) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (NAGLU) - PM1. The variant is present at low allele frequencies population databases (rs104894601 – gnomAD 0.0003188%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Arg234Cys) was detected in trans with a pathogenic variant (PMID: 11286389; PMID: 30070758) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic -

Nov 20, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The NAGLU c.700C>T (p.Arg234Cys) variant located in the alpha-n-acetylglucosaminidase, tim-barrel domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 10/276804 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000361, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). Multiple publications have cited the variant in compound heterozygote and homozygote MPS IIIB pts and found NAGLU activity to be significantly decreased (Mangas_2008). In addition, a reputable database, OMIM classifies the variant as "pathogenic." Taken together, this variant is classified as pathogenic. -

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

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:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 234 of the NAGLU protein (p.Arg234Cys). This variant is present in population databases (rs104894601, gnomAD 0.02%). This missense change has been observed in individual(s) with NAGLU-related conditions (PMID: 9832037, 11286389, 18218046, 23380547, 30070758). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1572). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.

PhyloP100

3.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.5

D;.

REVEL

Pathogenic

0.93

Sift

Benign

0.032

D;.

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.96

Loss of MoRF binding (P = 0.0473);.;

MVP

0.99

MPC

1.4

ClinPred

0.93

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.94

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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