rs104894592

Positions:

chr17-42541074-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000263.4(NAGLU):c.889C>T(p.Arg297*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,614,028 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

NAGLU
NM_000263.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

Conservation

PhyloP100: -0.0600

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 links:

ENSG00000266929 (HGNC:):

ENSG00000266929 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-42541074-C-T is Pathogenic according to our data. Variant chr17-42541074-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42541074-C-T is described in Lovd as [Pathogenic]. Variant chr17-42541074-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGLU	NM_000263.4 link	c.889C>T	p.Arg297*	stop_gained	5/6	ENST00000225927.7	NP_000254.2	P54802A0A140VJE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGLU	ENST00000225927.7 link	c.889C>T	p.Arg297*	stop_gained	5/6	1	NM_000263.4	ENSP00000225927.1		P54802

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251488

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

205

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000172

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001562). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2000	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The NAGLU c.889C>T (p.Arg297Ter) variant is a stop-gained variant and has been reported in at least eight studies in which it is found in a total of 26 individuals with mucopolysaccharidosis, type III including three in a homozygous state, 20 in a compound heterozygous state, and three in a heterozygous state where the second allele was not identified (Zhao et al. 1996; Beesley et al. 1998; Weber et al. 1999; Yogalingham et al. 2000; Valstar et al. 2010; de Ruijter et al. 2012; Pollard et al. 2013; Welling et al. 2015). The p.Arg297Ter variant was absent from 80 control alleles but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant resulted in very low levels of NAGLU enzyme activity and a 12-fold increase in glycosaminoglycan storage in individual fibroblasts compared to normal fibroblasts (Yogalingham et al. 2000). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Agr297Ter variant is classified as pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 05, 2021	PVS1, PS3, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2018	Variant summary: NAGLU c.889C>T (p.Arg297X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.1597C>T (p.Arg533X) has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.8e-05 in 277224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NAGLU causing Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (5.8e-05 vs 0.0025), allowing no conclusion about variant significance. The variant, c.889C>T, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(Bunge_1999, Heron_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. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) ctie the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Reported as a common pathogenic variant in association with MPSIIIB (Pollard et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate when R297X is expressed in CHO-K1 cells, only a truncated polypeptide that is rapidly degraded is observed, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay, and no detectable enzyme activity is present (Yogalingam et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23084433, 25525159, 20852935, 9832037, 8650226, 29979746, 29620724, 9443875, 11068184, 22976768, 26907177, 10094189, 25256447, 28751108, 28836185, 32578945, 31980526) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 25, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg297*) in the NAGLU gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAGLU are known to be pathogenic (PMID: 9832037, 10094189, 16151907). This variant is present in population databases (rs104894592, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 22976768, 28836185). ClinVar contains an entry for this variant (Variation ID: 1562). For these reasons, this variant has been classified as Pathogenic. -

Mucopolysaccharidosis

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.48

Vest4

0.79

GERP RS

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over