rs1553917428

Variant names:

• chr4-1002946-T-G
• rs1553917428
• NM_000203.5:c.1402+2T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP4_Moderate PM3 PM2_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1402+2T>G variant alters the canonical donor splice site dinucleotide of intron 9 of IDUA. This variant is predicted to result in skipping of biologically-relevant-exon 9 (IDUA has 14 exons), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes (0.2-3.4 versus normal range 27.2–52 nmol/h/mg protein), and clinical features specific to MPS I including macrocephaly, arthropathy, hepatomegaly, and airway disease. These patients also had documented increased urinary excretion of HS and DS. Thus three areas are met, giving the evidence to meet PP4 at the moderate level (PP4_Moderate). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927). The variants were confirmed to be in trans by parental testing (PMID:21480867) (1 point). Another patient is compound heterozygous for the variant and c.98A>C (p.His33Pro). This variant has not yet been classified by the ClinGen LD VCEP. The allelic data from the second patient will be used in the classification of p.His33Pro and is not included here to avoid circular logic. Total points for PM3 = 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002819 (3/1064228 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Two additional variants at this canonical splice donor site c.1402+1G>A and c.1402+1G>T) have been classified as likely pathogenic by the ClinGen LD VCEP. However PS1 does not apply (Table 2, PMID:37352859). There is a ClinVar entry for this variant (ClinVar Variation ID: 553131). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1_Strong, PM3, PM2_Supporting(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355964392/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: IDUA NM_000203.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.575
• Publications: 0 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: ClinGen, Myriad Women’s Health
• Scheie syndrome

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

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1402+2T>G		splice_donor_variant, intron_variant	Intron 9 of 13	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1006+2T>G		splice_donor_variant, intron_variant	Intron 8 of 12		NP_001350505.1
IDUA	NR_110313.1	n.1490+2T>G		splice_donor_variant, intron_variant	Intron 9 of 13
IDUA	XM_047415650.1	c.1402+2T>G		splice_donor_variant, intron_variant	Intron 9 of 11		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1402+2T>G		splice_donor_variant, intron_variant	Intron 9 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1208790 Hom.: 0 Cov.: 36 AF XY: 0.00000171 AC XY: 1 AN XY: 586314

⚠️ 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: 23658

American (AMR) AF: 0.00 AC: 0 AN: 10194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16922

East Asian (EAS) AF: 0.00 AC: 0 AN: 27248

South Asian (SAS) AF: 0.00 AC: 0 AN: 51364

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000301 AC: 3 AN: 996412

Other (OTH) AF: 0.00 AC: 0 AN: 49748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Apr 21, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.1402+2T>G variant alters the canonical donor splice site dinucleotide of intron 9 of IDUA. This variant is predicted to result in skipping of biologically-relevant-exon 9 (IDUA has 14 exons), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). Two patients with this variant had documented IDUA deficiency within the affected range in leukocytes (0.2-3.4 versus normal range 27.2–52 nmol/h/mg protein), and clinical features specific to MPS I including macrocephaly, arthropathy, hepatomegaly, and airway disease. These patients also had documented increased urinary excretion of HS and DS. Thus three areas are met, giving the evidence to meet PP4 at the moderate level (PP4_Moderate). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP, c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927). The variants were confirmed to be in trans by parental testing (PMID: 21480867) (1 point). Another patient is compound heterozygous for the variant and c.98A>C (p.His33Pro). This variant has not yet been classified by the ClinGen LD VCEP. The allelic data from the second patient will be used in the classification of p.His33Pro and is not included here to avoid circular logic. Total points for PM3 = 1 point (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000002819 (3/1064228 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Two additional variants at this canonical splice donor site c.1402+1G>A and c.1402+1G>T) have been classified as likely pathogenic by the ClinGen LD VCEP. However PS1 does not apply (Table 2, PMID: 37352859). There is a ClinVar entry for this variant (ClinVar Variation ID: 553131). In summary, this variant meets the criteria to be classified as likely pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0.): PVS1_Strong, PM3, PM2_Supporting (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 21, 2025) -

Aug 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 553131). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21480867). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 9 of the IDUA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). -

Hurler syndrome Pathogenic:1

Jul 28, 2017

Counsyl

Significance: Pathogenic

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.69	D
PhyloP100		0.57
GERP RS		4.3
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs1553917428; hg19: chr4-996734;