NM_000203.5:c.1205G>A

Variant names:

• chr4-1002747-G-A
• rs121965019
• NM_000203.5:c.1205G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1205G>A (p.Trp402Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 9 out of a total of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Complete loss of IDUA activity was confirmed when the variant was transiently expressed in COS-7 cells (PMID:11735025) (PVS1). This is the most common variant to be identified in patients with mucopolysaccharidosis type 1 (MPS1) in the United States (45% of alleles), Mexico (29%), Colombia (50%), Brazil (29%), the United Kingdom (45%), the Netherlands (42%), Germany (50%), the Czech Republic and Slovakia (33%), Spain (62%) and Australia (34%) (reviewed in PMID:29393969). At least 38 homozygotes (PMID:1301196, 28752568) (max PM3 points = 2 x 0.5 = 1 point for homozygotes), and at least 73 individuals who are compound heterozygous for the variant and a second variant in IDUA, including another well-known pathogenic variant, p.Gln70Ter, have been reported (PMID:1301941, 11735025, 28752568, 30809705). The allelic evidence from these compound heterozygous patients will be used to support the classification of the other variant and is not included here to avoid circular logic (PM3 based on evidence from homozygotes). Patients are reported with detailed clinical features of MPS I or elevated urine GAGs in addition to documentation of laboratory values showing deficient IDUA activity (PMID:1301941, 11735025, 30809705) (PP4). A knock in mouse, homozygous for a variant analogous to p.Trp402Ter (mouse Idua Trp392Ter) was reported to have a phenotype that closely correlates with features in humans patients with MPS1 (PMID:19751987). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001555 (1749/1124730 alleles) in the European non-Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) and lower than the threshold for BS1 (>0.0025). Therefore, no population codes are met. Additional data is available in the literature but the classification of pathogenic has already been reached. There is a ClinVar entry for this variant (Variation ID: 11908). In summary, this variant is the most frequently reported variant in individuals with MPS1 and meets the criteria to be classified as pathogenic for this disorder. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220498/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:31 O:2
• Conservation: PhyloP100: 0.133
• Publications: 181 publications found

Genes affected

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

IDUA Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1205G>A	p.Trp402*	stop_gained	Exon 9 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.809G>A	p.Trp270*	stop_gained	Exon 8 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1293G>A		non_coding_transcript_exon	Exon 9 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1205G>A	p.Trp402*	stop_gained	Exon 9 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1205G>A	p.Trp402*	stop_gained	Exon 9 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1280G>A	p.Trp427*	stop_gained	Exon 10 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.000860 AC: 130 AN: 151238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000585 AC: 53 AN: 90548 AF XY: 0.000489

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000430

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00131 AC: 1750 AN: 1334448 Hom.: 0 Cov.: 34 AF XY: 0.00130 AC XY: 852 AN XY: 657900

African (AFR) AF: 0.000111 AC: 3 AN: 26968

American (AMR) AF: 0.000495 AC: 15 AN: 30280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23654

East Asian (EAS) AF: 0.00 AC: 0 AN: 30054

South Asian (SAS) AF: 0.00 AC: 0 AN: 73662

European-Finnish (FIN) AF: 0.000328 AC: 11 AN: 33500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00155 AC: 1639 AN: 1056886

Other (OTH) AF: 0.00148 AC: 82 AN: 55508

GnomAD4 genome AF: 0.000859 AC: 130 AN: 151342 Hom.: 0 Cov.: 33 AF XY: 0.000744 AC XY: 55 AN XY: 73930

African (AFR) AF: 0.000316 AC: 13 AN: 41138

American (AMR) AF: 0.000197 AC: 3 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.000287 AC: 3 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 67844

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.000827

ESP6500AA AF: 0.000441 AC: 1

ESP6500EA AF: 0.000453 AC: 2

ExAC AF: 0.0000565 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Mucopolysaccharidosis type 1 (9)
8	-	-	not provided (8)
5	-	-	Hurler syndrome (5)
4	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (4)
2	-	-	Mucopolysaccharidosis, MPS-I-H/S (2)
2	-	-	See cases (2)
1	-	-	IDUA-related disorder (1)
1	-	-	Inborn genetic diseases (1)
-	-	-	Mucopolysaccharidosis type 1;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	46
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Benign	0.70	D
PhyloP100		0.13
Vest4		0.60
GERP RS		4.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965019; hg19: chr4-996535;