GeneBe

rs1230096882

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2_SupportingPP3PP4PM3_StrongPM4_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

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 7.85

Publications

4 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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
IDUANM_000203.5 linkc.1045_1047delGAC p.Asp349del conservative_inframe_deletion Exon 8 of 14 ENST00000514224.2 NP_000194.2 P35475-1
IDUANM_001363576.1 linkc.649_651delGAC p.Asp217del conservative_inframe_deletion Exon 7 of 13 NP_001350505.1
IDUAXM_047415650.1 linkc.1045_1047delGAC p.Asp349del conservative_inframe_deletion Exon 8 of 12 XP_047271606.1
IDUANR_110313.1 linkn.1133_1135delGAC non_coding_transcript_exon_variant Exon 8 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkc.1045_1047delGAC p.Asp349del conservative_inframe_deletion Exon 8 of 14 2 NM_000203.5 ENSP00000425081.2 P35475-1
IDUAENST00000247933.9 linkc.1045_1047delGAC p.Asp349del conservative_inframe_deletion Exon 8 of 14 1 ENSP00000247933.4 P35475-1
IDUAENST00000514698.5 linkn.1152_1154delGAC non_coding_transcript_exon_variant Exon 5 of 11 5
IDUAENST00000652070.1 linkn.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
show subpopulations
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
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33462
American (AMR)
AF:
0.00
AC:
0
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39684
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52862
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111692
Other (OTH)
AF:
0.00
AC:
0
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41458
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2
Apr 07, 2025
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

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). -

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. -

Hurler syndrome Pathogenic:2
Apr 16, 2018
Counsyl
Significance:Likely 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. -

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

- -

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

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.8
Mutation Taster
=6/94
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1230096882; hg19: chr4-996126; API