rs1226056948

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.

Score: 11 - Pathogenic

11

PP4_ModeratePVS1PM2_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: 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.300-3C>G		splice_region_variant, intron_variant	Intron 2 of 13	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.-97-3C>G		splice_region_variant, intron_variant	Intron 1 of 12		NP_001350505.1
IDUA	NR_110313.1	n.388-3C>G		splice_region_variant, intron_variant	Intron 2 of 13
IDUA	XM_047415650.1	c.300-3C>G		splice_region_variant, intron_variant	Intron 2 of 11		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.300-3C>G		splice_region_variant, intron_variant	Intron 2 of 13	2	NM_000203.5	ENSP00000425081.2

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Jun 30, 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 551563). This variant has been observed in individual(s) with mucopolysaccharidosis (PMID: 10735634, 29801497). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change falls in intron 2 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. It affects a nucleotide within the consensus splice site. -

May 23, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hurler syndrome Uncertain:1

Apr 18, 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. -

Computational scores

Source: dbNSFP v4.3

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;