4-1004313-C-T

Variant names:

• chr4-1004313-C-T
• rs756572099
• NM_000203.5:c.1882C>T

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PM3 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.1882C>T (p.Arg628Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). This variant has been detected in at least 16 individuals with MPS I. This variant has been detected in at least 17 individuals with MPS I. Of those individuals, 6 were compound heterozygous for the variant and a variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen LD VCEP, including c.236C>T (p.Ala79Val) (ClinVar Variation ID: 1458769) (PMID:27520059, LP, 0.25 pts); c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID:15081804, 25614311, 2 x 0.5 pts); c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID:12509712, 19396826, 19954743; one confirmed in trans, one unconfirmed, 1 + 0.5 pt) and c.2T>C (p.Met1?) (PMID:34813777, 0.5 pts). Ten individuals were homozygous for the variant (PMIDs: 27511503, 24798265, 21521498, 12203999, 11735025, 35141277, 35893030, 22718273, 35123515) (max 2 x 0.5 pt). Another proband was compound heterozygous for the variant and c.809T>G (p.Ile270Ser) (PMID:16435195); the allelic data from this patient has been used in the classification of p.Ile270Ser and is not included here to avoid circular logic. Total 4.25 pts (PM3_VeryStrong). At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and/or clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, and corneal involvement (PMIDs: 27520059, 21521498, 19396826, 11735025; PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00004459 (2/44852 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 550421). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_VeryStrong, PVS1_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on July 7, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802462/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.434
• Publications: 19 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

Our verdict: Pathogenic. The variant received 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1882C>T	p.Arg628*	stop_gained	Exon 14 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1486C>T	p.Arg496*	stop_gained	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1974C>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1882C>T	p.Arg628*	stop_gained	Exon 14 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1882C>T	p.Arg628*	stop_gained	Exon 14 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1957C>T	p.Arg653*	stop_gained	Exon 15 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248786 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459396 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726090

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.000579 Hom.: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
2	-	-	Hurler syndrome (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.59	D
PhyloP100		0.43
Vest4		0.75
GERP RS		4.7
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs756572099; hg19: chr4-998101;