Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000203.5(IDUA):c.152G>A (p.Gly51Asp)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA274902

193061 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5737252f-23b3-4e78-88c3-e5b8da58fdd7

Approved on: 2024-12-06

Published on: 2024-12-15

HGVS expressions

NM_000203.5:c.152G>A

NM_000203.5(IDUA):c.152G>A (p.Gly51Asp)

NC_000004.12:g.987236G>A

CM000666.2:g.987236G>A

NC_000004.11:g.981024G>A

CM000666.1:g.981024G>A

NC_000004.10:g.971024G>A

NG_008103.1:g.5240G>A

NG_033042.1:g.11201C>T

ENST00000247933.9:c.152G>A

ENST00000514224.2:c.152G>A

ENST00000247933.8:c.152G>A

ENST00000398520.6:c.576+3892C>T

ENST00000502910.5:c.152G>A

ENST00000504568.5:c.150G>A

ENST00000506561.5:n.161G>A

ENST00000508168.5:n.171G>A

ENST00000514698.5:n.193G>A

ENST00000622731.4:c.576+3892C>T

NM_000203.4:c.152G>A

NM_134425.2:c.576+3892C>T

NR_110313.1:n.240G>A

NM_134425.3:c.576+3892C>T

NM_134425.4:c.576+3892C>T

Pathogenic

PM3_Very Strong PP3_Moderate PM2_Supporting PP4

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000203.5(IDUA):c.152G>A variant in IDUA is predicted to result in a missense substitution, p.Gly51Asp. This variant has been reported in 9-13% of Italian MPS1 alleles (PMID: 9427149, 12203999, 21394825), and has been identified in patients from other European countries as well as Iran, Egypt, and India (PMID: 19839758, 31298590, 33301762). When reported, the diagnosis confirmed by deficiency of iduronidase activity (PMID: 7951228, 9427149, 12203999, 21394825) including one patient with detailed clinical features and residual enzyme activity values provided (PMID: 33301762) (PP4). At least 7 patients are homozygous for the variant (PMIDs: 9427149, 12203999, 19839758, 21394825, 31298590, 33301762). In addition, at least 6 patients are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, all phase unknown, including c.208C>T (p.Gln70Ter) (2 patients, PMID: 12203999), c.1205G>A (p.Trp402Ter) (PMID: 7951228), and c.1598C>G (p.Pro533Arg) (at least 2 patients, PMID: 9427149, 12203999, 21394825), and c.1163delC (PMID: 12203999) (PM3_Very Strong). Further patients have been reported who are compound heterozygous for the variant but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID: 9427149, 12203999, 21394825). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002447 (2/81730 alleles) in the South Asian 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 0.914 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 (PP3_Moderate). SpliceAI predicts no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 193061). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

PM3_Very Strong

At least 7 patients are homozygous for the variant including Indian, Iranian, Egyptian, and Italian patients (PMIDs: 9427149, 12203999, 19839758, 21394825, 31298590, 33301762) (max 2 x 0.5 points). In addition, at least 6 patients are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, all phase unknown, including c. 208C>T (p.Gln70Ter) (phase unknown, 2 patients, 2 x 0.5 points, PMID: 12203999), c.1205G>A (p.Trp402Ter) (PMID: 7951228, 0.5 points), and c.1598C>G (p.Pro533Arg) (at least 2 patients, max 2 x 0.5 points, PMID: 9427149, 12203999, 21394825), and c.1163delC (PMID: 12203999). 4 points (PM3_Very Strong). Further patients have been reported who are compound heterozygous for the variant but the allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic (PMID: 9427149, 12203999, 21394825).

PP3_Moderate

The computational predictor REVEL gives a score of 0.914 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 (PP3_Moderate). SpliceAI predicts no impact on splicing.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002447 (2/81730 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

PP4

This variant has been reported in 9-13% of Italian MPS1 alleles (PMID: 9427149, 12203999, 21394825), and has been identified in patients from other European countries as well as Iran, Egypt, and India (PMID: 19839758, 31298590, 33301762). When reported, the diagnosis confirmed by deficiency of iduronidase activity (PMID: 7951228, 9427149, 12203999, 21394825) including one patient with detailed clinical features and residual enzyme activity values provided (PMID: 33301762) (PP4).

Curation History

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