NM_000203.5:c.300-3C>G

Variant names:

• chr4-1000609-C-G
• rs1226056948
• NM_000203.5:c.300-3C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4_Moderate PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.300-3C>G variant in IDUA occurs within the splice acceptor region of intron 2. RT-PCR of fibroblast RNA from an individual who is compound heterozygous for the variant (labeled as 388-3C>G in the publication) revealed that the variant results in insertion of 58 intronic nucleotides, which would result in a frameshift). Analysis of heterozygous polymorphic markers showed that the variant caused a significant decrease in the level of IDUA mRNA derived from the allele with the c.300-3C>G variant. Furthermore, expression of the variant in COS-7 cells resulted in 1.6% wild type IDUA activity with no IDUA protein detected on western blot (PMID:10735634) (PVS1). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes, urinary GAGs above the normal range, or clinical features specific to MPS I including hepatosplenomegaly, corneal involvement, skeletal and cardiac abnormalities (PMID:10735634, 29801497). (PP4_Moderate). These individuals are compound heterozygous for the variant and another variant in IDUA, c.1037T>G or c.1874A>C) (PMID:10735634, 29801497). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PM3 not applied). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004557 (2/44876 alleles) in the EAS population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). 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): PVS1, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 23, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA549265042/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDUA NM_000203.5 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 0.849
• Publications: 5 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 11 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.
• 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.300-3C>G		splice_region intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.-97-3C>G		splice_region intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.388-3C>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.300-3C>G		splice_region intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.300-3C>G		splice_region intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.375-3C>G		splice_region intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250066 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458674 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44714

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

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110304

Other (OTH) AF: 0.00 AC: 0 AN: 60288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (2)
-	1	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.58
PhyloP100		0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1226056948; hg19: chr4-994397;