Variant: NM_000203.5(IDUA):c.501C>G (p.Tyr167Ter)

CA220511

92644 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 9d870c62-39a1-4e38-93a5-51813f713d21

Approved on: 2025-03-18

Published on: 2025-03-18

HGVS expressions

NM_000203.5:c.501C>G
NM_000203.5(IDUA):c.501C>G (p.Tyr167Ter)
NC_000004.12:g.1001475C>G
CM000666.2:g.1001475C>G
NC_000004.11:g.995263C>G
CM000666.1:g.995263C>G
NC_000004.10:g.985263C>G
NG_008103.1:g.19479C>G
ENST00000247933.9:c.501C>G
ENST00000514224.2:c.501C>G
ENST00000652070.1:n.557C>G
ENST00000247933.8:c.501C>G
ENST00000502910.5:c.360C>G
ENST00000504568.5:c.461C>G
ENST00000509948.5:c.294C>G
ENST00000514192.5:c.318C>G
ENST00000514224.1:c.105C>G
ENST00000514698.5:n.401C>G
NM_000203.4:c.501C>G
NR_110313.1:n.589C>G
NM_001363576.1:c.105C>G

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM2_Supporting PM3_Supporting

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000203.5:c.501C>G (p.Tyr167Ter) variant is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5 out of 14, leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism (PVS1; PMID 28676128). An Algerian patient, diagnosed with severe MPS I, has been reported with elevated urine GAGs, IDUA deficiency, and clinical features consistent with the condition (PMID: 27196898) (PP4_Moderate). This patient is homozygous for the variant (PMID: 27196898) (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is [8.476e-7] (1/ 1179740 alleles) in the European non-Finnish 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: 92644). 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): PVS1, PP4_Moderate, PM2_Supporting, PM3_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 18, 2025)

Met criteria codes

• PVS1: The NM_000203.5:c.501C>G (p.Tyr167Ter) variant is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 5 out of 14, leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 28676128).
• PP4_Moderate: An Algerian patient, diagnosed with severe MPS I, has been reported with elevated urine GAGs, IDUA deficiency, and clinical features consistent with the condition, meeting PP4_Moderate (PMID: 27196898).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is [8.476e-7] (1/ 1179740 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (< 0.00025), meeting this criterion (PM2_Supporting).
• PM3_Supporting: One Algerian patient diagnosed with severe MPS I is homozygous for the variant (PMID: 27196898)