The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: IDUA vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000203.5(IDUA):c.1614del (p.His539fs)

CA234129

167191 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
UUID: 98bf998c-00fc-4ac7-a520-d7c75b4de17d
Approved on: 2024-12-05
Published on: 2025-03-20

HGVS expressions

NM_000203.5:c.1614del
NM_000203.5(IDUA):c.1614del (p.His539fs)
NC_000004.12:g.1003434del
CM000666.2:g.1003434del
NC_000004.11:g.997222del
CM000666.1:g.997222del
NC_000004.10:g.987222del
NG_008103.1:g.21438del
ENST00000247933.9:c.1614del
ENST00000514224.2:c.1614del
ENST00000652070.1:n.1670del
ENST00000247933.8:c.1614del
ENST00000514224.1:c.1218del
ENST00000514417.1:n.6del
ENST00000514698.5:n.1721del
NM_000203.4:c.1614del
NR_110313.1:n.1702del
NM_001363576.1:c.1218del
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Pathogenic

Met criteria codes 4
PM2_Supporting PVS1 PP4 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000203.5:c.1614del (p.His539ThrfsTer21) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 4 individuals with MPS I, with documented IDUA deficiency within the affected range in leukocytes (PMID: 8213840, 15300847, 19396826, 35141277) and/or clinical features specific to MPS I including short stature, joint stiffness, progressive developmental decline, severe hepatosplenomegaly, systolic murmur, mitral valve defects, umbilical hernia, hirsutism, large tongue, corneal clouding (PMID: 15300847, 19396826) (PP4). Of these individuals, at least 3 were compound heterozygous for the variant and another variant in IDUA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 8213840, 15300847, 35141277, 2 or 3 patients; max 2 x 0.5 points), and c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 25614311, 0.5 points). Another patient is compound heterozygous for the variant and c.1650+5G>A (PMID: 19396826). The allelic data from this patient will be used in the classification of c.1650+5G>A and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001741 (2/1148676 alleles) in the NFE population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 167191). 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, PM2_Supporting, PM3_Moderate, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001741 (2/1148676 alleles) in the NFE population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
PVS1
The NM_000203.5:c.1614del (p.His539ThrfsTer21) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11/14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
PP4
At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes (PMID: 8213840, 15300847, 19396826, 35141277) and/or clinical features specific to MPS I including short stature, joint stiffness, progressive developmental decline, severe hepatosplenomegaly, systolic murmur, mitral valve defects, umbilical hernia, hirsutism, large tongue, corneal clouding (PMID: 15300847, 19396826) (PP4)
PM3
At least 3 patients were compound heterozygous for the variant and another variant in IDUA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 8213840, 15300847, 35141277, max 2 x 0.5 points), and c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 25614311, 0.5 points). Another patient is compound heterozygous for the variant and c.1650+5G>A (PMID: 19396826). The allelic data from this patient will be used in the classification of c.1650+5G>A and is not included here to avoid circular logic. Total 1.5 points (PM3).
Curation History
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