Variant: NM_000203.5(IDUA):c.1898C>G (p.Ser633Trp)

CA10605410

286242 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: fa57b8eb-1a95-4f2d-aeca-d45cd559e888

Approved on: 2024-12-06

Published on: 2025-06-08

HGVS expressions

NM_000203.5:c.1898C>G
NM_000203.5(IDUA):c.1898C>G
NM_000203.5(IDUA):c.1898C>G (p.Ser633Trp)
NC_000004.12:g.1004329C>G
CM000666.2:g.1004329C>G
NC_000004.11:g.998117C>G
CM000666.1:g.998117C>G
NC_000004.10:g.988117C>G
NG_008103.1:g.22333C>G
ENST00000247933.9:c.1898C>G
ENST00000514224.2:c.1898C>G
ENST00000652070.1:n.1954C>G
ENST00000247933.8:c.1898C>G
ENST00000514224.1:c.1502C>G
ENST00000514698.5:n.2009C>G
NM_000203.4:c.1898C>G
NR_110313.1:n.1990C>G
NM_001363576.1:c.1502C>G

Likely Pathogenic

• Met criteria codes: PP3_Moderate PM3 PP4 PM2_Supporting

• Not Met criteria codes: PM5

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.1898C>G variant in IDUA is a missense variant predicted to cause substitution of serine by tryptophan at amino acid 633 (p.Ser633Trp). This variant has been detected in at least 4 individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (phase not confirmed, 0.5 points, PMID: 24798265). Three individuals were homozygous for the variant (max 1 point, PMIDs: 24798265, 33389473). Total: 1.5 points (PM3). One of these patients had documented IDUA deficiency within the affected range in dried blood spot and clinical features specific to MPS I including dysostosis multiplex, arthropathy, and corneal involvement (PMID: PMID: 33389473) (PP4). The computational predictor REVEL gives a score of 0.871 which is above the threshold of 0.773 (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another variant at the same amino acid position, p.Ser633Leu, has been reported in individuals with MPS I (PMID: 11735025, 21480867. This variant has not yet been classified by the ClinGen LD VCEP, therefore, PM5 was not applied. There is a ClinVar entry for this variant (Variation ID: 286242). In summary, this variant meets the criteria to be classified as likely 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 1.1.0): PM3, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024).

Met criteria codes

• PP3_Moderate: The computational predictor REVEL gives a score of 0.871 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)
• PM3: This variant has been detected in at least 4 individuals with MPS I. Of those individuals, 1 was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (phase not confirmed, 0.5 points, PMID: 24798265). Three individuals were homozygous for the variant (0.5 points each, total points from homozygotes limited to 1, PMIDs: 24798265, 33389473). Total: 1.5 points (PM3).
• PP4: At least 1 patient with this variant had documented IDUA deficiency within the affected range in dried blood spot and clinical features specific to MPS I including dysostosis multiplex, arthropathy, and corneal involvement (PP4).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60010 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PM5: Another variant at the same amino acid position, p.Ser633Leu, has been reported in individuals with MPS I (PMID: 11735025, 21480867. This variant has not yet been classified by the ClinGen LD VCEP, therefore, PM5 was not applied.