chr17-42541185-G-T

Variant names:

• chr17-42541185-G-T
• rs749140168
• NM_000263.4:c.1000G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_000263.4(NAGLU):​c.1000G>T​(p.Val334Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,460,936 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V334I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NAGLU NM_000263.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 5.39
• Publications: 8 publications found

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

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000263.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42541185-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 623899.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-42541185-G-T is Pathogenic according to our data. Variant chr17-42541185-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 553204.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	NM_000263.4	MANE Select	c.1000G>T	p.Val334Phe	missense	Exon 5 of 6	NP_000254.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGLU	ENST00000225927.7	TSL:1 MANE Select	c.1000G>T	p.Val334Phe	missense	Exon 5 of 6	ENSP00000225927.1
	NAGLU	ENST00000592454.1	TSL:2	c.94G>T	p.Val32Phe	missense	Exon 1 of 2	ENSP00000468665.1
	NAGLU	ENST00000591587.1	TSL:5	c.360-1843G>T		intron	N/A	ENSP00000467836.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460936 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Likely pathogenic

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

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-B;C5569050:Charcot-Marie-Tooth disease axonal type 2V Pathogenic:1

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 334 of the NAGLU protein (p.Val334Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 10094189). ClinVar contains an entry for this variant (Variation ID: 553204). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function with a positive predictive value of 95%. This variant disrupts the p.Val334 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been observed in individuals with NAGLU-related conditions (PMID: 10094189, 33747789), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Mucopolysaccharidosis, MPS-III-B Uncertain:1

Aug 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mucopolysaccharidosis Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.84		Loss of glycosylation at T332 (P = 0.0921)
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.1
PromoterAI		-0.011	Neutral
Varity_R		0.93
gMVP		0.96
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs749140168; hg19: chr17-40693203;