rs104894592

chr17-42541074-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000263.4(NAGLU):c.889C>T(p.Arg297Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: -0.0600

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]

ACMG classification

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	UniProt
NAGLU	NM_000263.4	c.889C>T	p.Arg297Ter	stop_gained	5/6	ENST00000225927.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGLU	ENST00000225927.7	c.889C>T	p.Arg297Ter	stop_gained	5/6	1	NM_000263.4	P1
NAGLU	ENST00000586516.5	c.493C>T	p.Arg165Ter	stop_gained	4/4	2
NAGLU	ENST00000591587.1	c.360-1954C>T		intron_variant		5
NAGLU	ENST00000592454.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152142 Hom.: 0 Cov.: 31

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: 14 AN: 251488 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135916

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.: 0 Cov.: 32 AF XY: 0.000138 AC XY: 100 AN XY: 727244

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: 15 AN: 152142 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74320

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.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B Pathogenic:11

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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, 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]. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 19, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2000	- -
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	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
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	- -
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) -

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	Invitae	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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.48	N
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs104894592; hg19: chr17-40693092; COSMIC: COSV56795594; COSMIC: COSV56795594;