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: 2024-12-06

Published on: 2024-12-16

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: PM2_Supporting PP4_Moderate PVS1 PM3

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). 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). This variant has been detected in at least two individuals with MPS I. Of those individuals, one individual was homozygous for the variant (PMID: 27196898), one was compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (c.208C>T, p.Gln70Ter, phase unconfirmed), which has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PMID: 19396826) (PM3_Moderate). At least two patients with this variant had documented IDUA deficiency within the affected range in leukocytes, or urinary GAGs expressed as either total GAGs or specific GAG elevation above the normal range, and clinical features specific to MPS I, including dysostosis multiplex, hepatosplenomegaly, arthropathy, corneal involvement (PMID: 19396826, 27196898) (PP4_Moderate). 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, PM3_Moderate. PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

Met criteria codes

• 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).
• PP4_Moderate: At least 2 patients with this variant had documented IDUA deficiency within the affected range in leukocytes, or urinary GAGs expressed as either total GAGs or specific GAG elevation above normal range, and clinical features specific to MPS I, including dysostosis multiplex, hepatosplenomegaly, arthropathy, or corneal involvement (PMID: 19396826, 27196898) (PP4_Moderate).
• 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).
• PM3: This variant has been detected in at least three individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and the pathogenic variant (c.208C>T, p.Gln70Ter, phase unconfirmed), which has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (PMID: 19396826, 0.5 points). One individual was homozygous for the variant (PMID: 27196898, 0.5 points). One patient was compound heterozygous for c.501C>G (p.Tyr167Ter), and c.614G>A (p.Cys205Tyr) (LP based on classification by the ClinGen Lysosomal Diseases VCEP) phase confirmed in trans by parental testing (PMID: 11735025). The allelic data from this patient was used in the classification of the missense change and is not included here to avoid circular logic. (0 points). (PM3_Moderate).