Variant: NM_000203.5(IDUA):c.713T>A (p.Leu238Gln)

CA2802065

265418 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: ad7a1cc0-9729-47b5-97d2-68b18c4abe70

Approved on: 2024-12-06

Published on: 2025-06-08

HGVS expressions

NM_000203.5(IDUA):c.713T>A
NM_000203.5:c.713T>A
NM_000203.5(IDUA):c.713T>A (p.Leu238Gln)
NC_000004.12:g.1001802T>A
CM000666.2:g.1001802T>A
NC_000004.11:g.995590T>A
CM000666.1:g.995590T>A
NC_000004.10:g.985590T>A
NG_008103.1:g.19806T>A
ENST00000247933.9:c.713T>A
ENST00000514224.2:c.713T>A
ENST00000652070.1:n.769T>A
ENST00000247933.8:c.713T>A
ENST00000502910.5:c.572T>A
ENST00000509948.5:c.506T>A
ENST00000514192.5:c.530T>A
ENST00000514224.1:c.317T>A
ENST00000514698.5:n.613T>A
NM_000203.4:c.713T>A
NR_110313.1:n.801T>A
NM_001363576.1:c.317T>A

Pathogenic

• Met criteria codes: PM2_Supporting PP3_Moderate PP4_Moderate PM3_Very Strong

• Not Met criteria codes: PM5 PS3

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.713T>A variant in IDUA is a missense variant predicted to cause substitution of Leu by Gln at amino acid 238 (p.Leu238Gln). This variant has been detected in at least 18 individuals with MPS I, the majority of whom had phenotypes consistent with a clinical diagnosis of Hurler-Scheie (PMID: 32188113, 31839529, 34984346, 26260077, 28125077, and others). All of those individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases; it is unknown if these variants were confirmed in trans. For example, in compound heterozygous patients, the second variant is p.Gln70Ter (1 patient, 0.5 points, PMID: 31194252), p.Trp402Ter (2 patients, 2 x 0.5 points, PMID: 31194252), c.386-2A>G (1 patient 0.5 points, PMID: 31194252), p.Glu182Lys (1 patient, 0.5 points, PMID: 31194252), Int3-2a>g (1 patient, 0.5 points, PMID: 31839529) and 63del (one patient, 0.5 points, PMID: 31839529) Total 4 points (PM3_VeryStrong). One of these individuals was an adult male with clinical features consistent with MPS I including coarse facial features, joint stiffness, heart murmur, mitral and aortic stenosis, retinal degeneration and optic disc edema, and ventriculomegaly, elevated urine keratan sulfate and dermatan sulfate, undetectable serum IDUA activity (PMID: 34984346) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004 (3/74,858 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another missense variant c.713T>C p.Leu238Pro in the same codon has been reported in the ClinVar database in association with MPS I (ClinVar Variation ID 1517837). However, this variant has not yet been evaluated by the ClinGen Lysosomal Diseases VCEP (PM5 not met). Expression of the variant in CHO cells showed 5.88% wild type IDUA activity (PMID: 15300847). However, this result does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP to apply PS3_Supporting criterion because the activity level was above the threshold of <2% established for this assay. The computational predictor REVEL gives a score of 0.904, 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). There is a ClinVar entry for this variant (Variation ID: 265418). 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 1.0.0): PM3_Very Strong, PP3_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 0.00004 (3/74,858 alleles) in the African/African American 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 0.904, 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_Moderate: Reported in compound heterozygous state with p.Trp402* in a 32-yo man with developmental delay with loss of abilities since 17 years of age, exertional dyspnea, coarse facial features, limited range of motion in extremities, stiff gait, murmur, mitral and aortic stenosis, retinal degeneration and optic disc edema, ventriculomegaly. Histopathology showed GAG accumulation in macrophage cytoplasm and valve stroma. Elevated urine keratan sulfate and dermatan sulfate. Serum enzyme activity showed undetectable alpha-L-iduronidase activity. ERT has improved peripheral symptoms and QoL. (PMID: 34984346) (PP4_Moderate).
• PM3_Very Strong: This variant has been detected in at least 18 individuals with MPS I, the majority of whom had phenotypes consistent with a clinical diagnosis of Hurler-Scheie (PMID: 32188113, 31839529, 34984346, 26260077, 28125077, and others). All of those individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PM3_Very Strong). For example, in compound heterozygous patients, the second variant is p.Gln70Ter (1 patient, 0.5 points, PMID: 31194252), p.Trp402Ter (2 patients, 2 x 0.5 points, PMID: 31194252), c.386-2A>G (1 patient 0.5 points, PMID: 31194252), p.Glu182Lys (1 patient, 0.5 points, PMID: 31194252), Int3-2a>g (1 patient, 0.5 points, PMID: 31839529) and 63del (one patient, 0.5 points, PMID: 31839529) Total 4 points (PM3_VeryStrong)

Not Met criteria codes

• PM5: Another missense variant c.713T>C p.Leu238Pro in the same codon has been reported in the Clinvar database in association with MPS I (ClinVar Variation ID 1517837). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP (PM5 not met). c.713T>C p.Leu238Pro considerations: REVEL 0.936 (PP4_Moderate). Clinvar LPx1 (Invitae 2021). Single allele in gnomAD (6.23e-7) (PM2_Supporting). No probands identified in the literature.
• PS3: Expression of the variant in CHO cells showed 5.88% wild type IDUA activity (PMID: 15300847). However, this result does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP to apply PS3_Supporting criterion because the activity level was above the threshold of <2% established for this assay. NB: the wrong c. nomenclature was used in this publication; however p. nomenclature was correct.