Variant: NM_000203.5(IDUA):c.1487C>G (p.Pro496Arg)

CA2802275

496861 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 6d174446-2fad-428b-8dc3-873c338fe8af

Approved on: 2024-12-05

Published on: 2025-03-19

HGVS expressions

NM_000203.5:c.1487C>G
NM_000203.5(IDUA):c.1487C>G (p.Pro496Arg)
NC_000004.12:g.1003120C>G
CM000666.2:g.1003120C>G
NC_000004.11:g.996908C>G
CM000666.1:g.996908C>G
NC_000004.10:g.986908C>G
NG_008103.1:g.21124C>G
ENST00000247933.9:c.1487C>G
ENST00000514224.2:c.1487C>G
ENST00000652070.1:n.1543C>G
ENST00000247933.8:c.1487C>G
ENST00000502829.1:n.289C>G
ENST00000514224.1:c.1091C>G
ENST00000514698.5:n.1594C>G
NM_000203.4:c.1487C>G
NR_110313.1:n.1575C>G
NM_001363576.1:c.1091C>G

Likely Pathogenic

• Met criteria codes: PM3_Strong PS3_Supporting PP4_Moderate PM2_Supporting PP3

• Not Met criteria codes: PM5 PM1 PS1

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.1487C>G variant in IDUA is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 496 p.(Pro496Arg). At least 8 patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.793G>C (p.Gly265Arg) (ClinVar Variation ID: 638074) (PMID: 21394825, LP, 0.25), c.152G>A (p.Gly51Asp) (ClinVar Variation ID: 193061) (PMID: 21394825, P, 2 x 0.5), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 21394825, P, 4 patients, max 2 x 0.5), and c.1598C>G (p.Pro533Arg) (PMID: 34408967, P, 0.5 points). One individual is homozygous for the variant (PMID: 34408967, 0.5 points). This variant has also been reported in compound heterozygosity with p.Arg89Trp (PMID: 21394825), c.1727+1G>A (PMID: 21394825), c.1854C>A (p.Tyr618Ter) (PMID: 27520059) and c.878_889dup (PMID 28752568). The allelic data from these patients will be used in the subsequent classification of then second variant and is not included here to avoid circular logic. Total 3.25 points (PM3_Strong). In one report (PMID: 27520059), there was evidence of decreased IDUA enzyme activity, increased urine glycosaminoglycans and a specific clinical phenotype, allowing for application of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000003515 (4/1137936 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). and has some experimental evidence suggesting absence of IDUA activity when the variant is expressed in Cos-7 cells (PMID: 11735025) (PS3_Supporting). Computational predictor tools (REVEL score 0.72) suggest that this variant may be deleterious to IDUA function (PP3). A different missense variant, c.1487C>G (p.Pro496Leu) [ClinVar Variation ID 551675] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen VCEP, however PM5 was not assigned to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 496861). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel: PM3_Strong, PP4_Moderate. PS3_Supporting, PM2_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

Met criteria codes

• PM3_Strong: Seven patients are compound heterozygous for the variants and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.793G>C (p.Gly265Arg) (ClinVar Variation ID: 638074) (PMID: 21394825, LP, 0.25), c.152G>A (p.Gly51Asp) (ClinVar Variation ID: 193061) (PMID: 21394825, P, 2 x 0.5), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 21394825, P, 4 patients, max 2 x 0.5). This variant has also been reported in compound heterozygosity with p.Arg89Trp (PMID: 21394825), c.1727+1G>A (PMID: 21394825), c.1854C>A (p.Tyr618Ter) (PMID: 27520059) and c.878_889dup (PMID 28752568). The allelic data from these patients will be used in the subsequent classification of then second variant and is not included here to avoid circular logic. Total 2.25 points (PM3_Strong).
• PS3_Supporting: Beesley et al. (PMID: 11735025) transfected COS-7 cells with either wild type or mutagenised IDUA cDNA constructs, including P496R. After subtracting background alpha-L-iduronidase activity in pR20.5-transfected COS-7 cells, cells with the P496R mutagenised cDNA construct had approximately 0.8% residual enzyme activity (<2% residual enzyme activity, hence meeting criteria for PS3_Supporting).
• PP4_Moderate: This variant has also been reported by Kwak et al. (PMID: 27520059) in combination with the variant c.1854C>A (p.Tyr618Ter), in a patient with deficient IDUA enzyme activity, increased urinary glycosaminoglycans and specific clinical features of MPSI (PP4_Moderate)
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.000003515 (4/1137936 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).
• PP3: The computational predictor REVEL gives a score of 0.72 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PMID: 36413997) (PP3).

Not Met criteria codes

• PM5: Another variant at this amino acid codon (c.1487C>T causing p.Pro496Leu) has been reported, and this variant has been classified by the ClinGen VCEP as likely pathogenic. However, the PM5 criterion will be used to contribute towards the c.1487C>T variant classification, and hence will not be used here.
• PM1: This variant does not involve one of the specific residues known to be crucial to the function of IDUA.
• PS1: No other established pathogenic variants are reported with the same amino acid change.