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 obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: IDUA CSPEC Genes: [ 'GAA' ] * Message MONDOs: MONDO:0001586 CSPEC MONDO: [ 'MONDO:0009290' ]


Variant: NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter)

CA2802166

550474 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
UUID: fc984f61-23fd-4353-bf5c-d2a11f5825f6
Approved on: 2024-12-05
Published on: 2025-03-03

HGVS expressions

NM_000203.5:c.1029C>G
NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter)
NC_000004.12:g.1002325C>G
CM000666.2:g.1002325C>G
NC_000004.11:g.996113C>G
CM000666.1:g.996113C>G
NC_000004.10:g.986113C>G
NG_008103.1:g.20329C>G
ENST00000247933.9:c.1029C>G
ENST00000514224.2:c.1029C>G
ENST00000652070.1:n.1085C>G
ENST00000247933.8:c.1029C>G
ENST00000514224.1:c.633C>G
ENST00000514698.5:n.1136C>G
NM_000203.4:c.1029C>G
NR_110313.1:n.1117C>G
NM_001363576.1:c.633C>G
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Pathogenic

Met criteria codes 4
PVS1 PM3_Strong PM2_Supporting PP4
Not Met criteria codes 3
PM5 PS1 PS3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
The NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter) variant is a nonsense variant observed to cause a premature stop codon in biologically relevant exon 8 (out of 14), leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism. Expression of the variant in COS-7 cells showed 1.1% of normal IDUA activity (PMID: 9391892) (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15956 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, 2 were heterozygous for the variant and a pathogenic or likely pathogenic variant (variants are: c.208C>T (p.Gln70Ter), c.3G>A (p.Met1?)), and one of those was confirmed in trans (PMIDs: 15081804, 9391892, 8019572) (PM3_Strong). At least 1 patient with this variant had undetectable IDUA activity in skin fibroblasts (PP4) (PMID: 15081804). There is a ClinVar entry for this variant (Variation ID: 550474). 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): PVS1, PM2_Supporting, PM3_Strong, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)
Met criteria codes
PVS1
The NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter) variant in IDUA is a nonsense variant observed to cause a premature stop codon in biologically relevant exon 8 out of 14, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. Expression of the variant in COS-7 cells showed 1.1% of normal IDUA activity (PMID: 9391892) (PVS1).
PM3_Strong
This variant has been detected in at least 3 individuals with MPS I. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (variants are: c.208C>T (p.Gln70Ter), c.3G>A (p.Met1Ile)), and one of those was confirmed in trans (2 points total; PMIDs: 15081804, 9391892, 8019572). No individuals were homozygous for the variant (PM3_Strong).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15956 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting).
PP4
At least 1 patient with this variant had documented IDUA deficiency within the affected range in fibroblasts (PP4).
Not Met criteria codes
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Expression of the variant in COS-7 cells showed 1.1% of normal IDUA activity. However, this assay does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP because this variant also meets the PVS1 criterion.
Curation History
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