chr4-1002338-AACG-A

Variant names:

• chr4-1002338-AACG-A
• rs1230096882
• NM_000203.5:c.1045_1047delGAC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3 PP4 PM2_Supporting PM1 PM3_Strong PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.1045_1047del (p.Asp349del) variant in IDUA is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid in a non-repeat region (p.Asp349del) (PM4_Supporting). This variant removes amino acid Asp349, a residue that has been shown to be important in substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID:23959878, 24036510) (PM1). At least 4 probands have been reported with the variant, all with a diagnosis of MPS I and including patients with very low IDUA activity, and elevated urine GAGs (PMID:36837830) or detailed clinical symptoms consistent with the condition (PMID:27351199) (PP4). Of those individuals, 2 were compound heterozygous, phase unknown, for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP; either c.713T>A (p.Leu238Gln) (PMID:27351199, 0.5 points) or c.208C>T (p.Gln70Ter) (PMID:21394825, 27392569, 0.5 points; cannot confirm that these reports are not the same patient). Two patients are homozygous for the variant (PMID:21394825, 36837830, 2 x 0.5 points). Total 2 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002229 (1/44872 alleles) in the East Asian population (PM2_Supporting). In silico predictors suggest that the variant impacts the function of the gene product; Mutation Taster predicts that the variant is "disease-causing", score for MutPredIndel is 0.789 (>0.5 for deleterious) (PP3). There is a ClinVar entry for this variant (Variation ID: 557885). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Strong, PM1, PP3, PM2_Supporting, PM4_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA438057772/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: IDUA NM_000203.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: 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.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1045_1047delGAC	p.Asp349del	conservative_inframe_deletion	Exon 8 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1045_1047delGAC	p.Asp349del	conservative_inframe_deletion	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1045_1047delGAC	p.Asp349del	conservative_inframe_deletion	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1152_1154delGAC		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1101_1103delGAC		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460862 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 726730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hurler syndrome Pathogenic:2

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis type 1 Pathogenic:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1045_1047del, results in the deletion of 1 amino acid(s) of the IDUA protein (p.Asp349del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.06%). This variant has been observed in individuals with mucopolysaccharidosis type I (PMID: 21394825, 27392569). ClinVar contains an entry for this variant (Variation ID: 557885). This variant disrupts a region of the IDUA protein in which other variant(s) (p.Asp349Tyr) have been determined to be pathogenic (PMID: 12203999, 12559846, 28752568, 30809705). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 03, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

May 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1230096882; hg19: chr4-996126;