Variant: NM_000203.5(IDUA):c.1163C>G (p.Thr388Arg)

CA91169370

496834 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: d4fdcccd-95c4-4d54-bbb4-92ca6e51ac0b

Approved on: 2024-12-06

Published on: 2025-06-07

HGVS expressions

NM_000203.5:c.1163C>G
NM_000203.5(IDUA):c.1163C>G (p.Thr388Arg)
NC_000004.12:g.1002459C>G
CM000666.2:g.1002459C>G
NC_000004.11:g.996247C>G
CM000666.1:g.996247C>G
NC_000004.10:g.986247C>G
NG_008103.1:g.20463C>G
ENST00000247933.9:c.1163C>G
ENST00000514224.2:c.1163C>G
ENST00000652070.1:n.1219C>G
ENST00000247933.8:c.1163C>G
ENST00000514224.1:c.767C>G
ENST00000514698.5:n.1270C>G
NM_000203.4:c.1163C>G
NR_110313.1:n.1251C>G
NM_001363576.1:c.767C>G

Likely Pathogenic

• Met criteria codes: PM3_Strong PP4 PM2_Supporting PP3_Moderate

• Not Met criteria codes: PM5 PM1

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.1163C>G variant in IDUA is a missense variant predicted to cause substitution of threonine by arginine at amino acid 388 (p.Thr388Arg). Two patients with this variant had IDUA deficiency within the affected range in leukocytes (specific values not provided) and clinical features specific to MPS I including corneal clouding (PMID: 17606547, 30120129). This variant has been detected in at least 10 individuals with MPS I who were heterozygous for the variant and a pathogenic or likely pathogenic variant classified by the ClinGen Lysosomal Diseases VCEP (variants: c.1139A>G, c.1205G>A, c.1855C>T, c.1861C>T); however, phase was not confirmed in any case (PMID: 14516901, 17606547, 21253827, 21963080, 28752568, 30120129) (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006003 (69/1149360 alleles) in the NFE population (gnomAD v2.1.1 is 0.00001342 with 1/74540 alleles in the NFE population), which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.824 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). 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 1.0.0): PM3_Strong, PM2_Supporting, PP3_Moderate, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

Met criteria codes

• PM3_Strong: This variant has been detected in at least 10 individuals with MPS I who were compound heterozygous for the variant and a pathogenic or likely pathogenic variant; however, phase was not confirmed. (Total of 2.75 pt for PM3_Strong) * 3 MPS I (2 H-S; 1 H) w/ IDUA p.Gln380Arg in unk phase (PMID: 17606547, 28752568, 30120129) (2 x 0.5 pt) * 4 MPS I (H) w/ IDUA p.Trp402X in unk phase (PMID: 14516901, 21253827, 28752568) (2 x 0.5 pt) * 1 MPS I (H) w/ IDUA p.Arg619X in unk phase (PMID: 28752568) (1 x 0.5 pt) * 1 MPS I (H) w/ IDUA p.Arg621X in unk phase (PMID: 21963080) (1 x 0.25 pt)
• PP4: 2 patient with this variant had documented IDUA deficiency within the affected range in leukocytes (specific values not provided) or clinical features specific to MPS I including corneal involvement. 0.5 pts; PP4 not met.
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006003 (69/1149360 alleles) in the NFE population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001342 (1/74540 alleles) in the NFE population, 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 0.824 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).

Not Met criteria codes

• PM5: ○ IDUA c.1163C>T p.Thr388Met is conflicted in ClinVar (Variation ID: 558615); LP by Invitae and VUS by Counsyl and PerkinElmer; at least 1 MPS I case; meets PM2_Supp ○ IDUA c.1163C>A p.Thr388Lys is conflicted in ClinVar (Variation ID: 198696); P by Invitae, LP by Broad, VUS by PerkinElmer and Counsyl; at least 1 MPS I case; meets PM2_Supp
• PM1: Not located in known functional domain.