Evidence Repository
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
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000203.5(IDUA):c.1087C>T (p.Arg363Cys)

CA2802184

557205 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 6ef65c5d-2676-4b8a-9235-634e48460b33
Approved on: 2024-12-06
Published on: 2024-12-16

HGVS expressions

NM_000203.5:c.1087C>T
NM_000203.5(IDUA):c.1087C>T (p.Arg363Cys)
NC_000004.12:g.1002383C>T
CM000666.2:g.1002383C>T
NC_000004.11:g.996171C>T
CM000666.1:g.996171C>T
NC_000004.10:g.986171C>T
NG_008103.1:g.20387C>T
ENST00000247933.9:c.1087C>T
ENST00000514224.2:c.1087C>T
ENST00000652070.1:n.1143C>T
ENST00000247933.8:c.1087C>T
ENST00000514224.1:c.691C>T
ENST00000514698.5:n.1194C>T
NM_000203.4:c.1087C>T
NR_110313.1:n.1175C>T
NM_001363576.1:c.691C>T
More

Likely Pathogenic

Met criteria codes 6
PM2_Supporting PP3_Moderate PP4 PM1 PM3_Supporting PS3_Moderate
Not Met criteria codes 1
PM5

Evidence Links 1

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.1087C>T variant in IDUA is predicted to result in the substitution of arginine by cysteine at amino acid 363 (p.Arg363Cys). This variant alters amino acid Arg363, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMIDs: 23959878, 24036510) (PM1). When the variant was expressed in CHO cells, no IDUA activity was detected, and synthesis and processing was abnormal (PMID: 15300847). The computational predictor REVEL gives a score of 0.845 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). Two patients with the variant have clinical symptoms consistent with MPS1 and one has "undetectable" IDUA activity (PMID: 15300847, 32781600). One of these patients is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP with unconfirmed phase, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 32781600). The other patient is compound heterozygous for the variant and c.1804T>A (p.Phe602Ile) (PMID: 15300847). The allelic data from this patient will be used in the classification of p.Phe602Ile and is not included here to avoid circular logic (PM3_Supporting). Another variant at the same amino acid position, c.1088G>A (p.Arg363His) has been identified in an individual with MPS 1 (PMID: 21734815). This variant has not yet been classified by the ClinGen LD VCEP. There is a Clinvar entry for this variant (Variation ID: 557205). In summary, this variant meet the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0): PM1, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting, PM3_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 0.000008485 (10/1178550 alleles) in the European non-Finnish population (GrpMax Filtering Allele Frequency, 95% confidence = 0.000004290), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
PP3_Moderate
The computational predictor REVEL gives a score of 0.845 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate).
PP4
Two patients with the variant have clinical symptoms consistent with MPS1 and one has "undetectable" IDUA activity (PMID: 15300847, 32781600).
PM1
This variant alters amino acid Arg363, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMIDs: 23959878, 24036510) (PM1).
PM3_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3_Moderate
When the variant was expressed in CHO cells, no IDUA activity was detected, and synthesis and processing was abnormal (PMID: 15300847)
IDUA sequence variants were engineered into wild-type IDUA cDNA by site-directed mutagenesis, then subcloned into an expression vector (pEFNeo). CHO cells were transfected with wild type or variant IDUA. IDUA enzyme activity was measured using the artificial substrate 4-MU-α-L-iduronic acid or with a radiolabeled disaccharide substrate derived from heparin. When the variant was expressed in CHO cells, no IDUA activity was detected, and synthesis and processing was abnormal (PMID: 15300847). PubMed:15300847
Not Met criteria codes
PM5
Another variant at the same amino acid position, c.1088G>A (p.Arg363His) has been identified in an individual with MPS 1 (PMID: 21734815).
Curation History
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