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.385+1G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA2801887

551966 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0e0b3cf5-5ad8-4e76-903d-2cc5af10f378

Approved on: 2024-12-05

Published on: 2025-03-03

HGVS expressions

NM_000203.5:c.385+1G>C

NM_000203.5(IDUA):c.385+1G>C

NC_000004.12:g.1000698G>C

CM000666.2:g.1000698G>C

NC_000004.11:g.994486G>C

CM000666.1:g.994486G>C

NC_000004.10:g.984486G>C

NG_008103.1:g.18702G>C

ENST00000247933.9:c.385+1G>C

ENST00000514224.2:c.385+1G>C

ENST00000652070.1:n.441+1G>C

ENST00000247933.8:c.385+1G>C

ENST00000502910.5:c.244+1G>C

ENST00000504568.5:c.345+1G>C

ENST00000506561.5:n.394+1G>C

ENST00000508168.5:n.263+1G>C

ENST00000509948.5:c.178+1G>C

ENST00000514192.5:c.202+1G>C

ENST00000514224.1:c.-12+1G>C

ENST00000514698.5:n.285+1G>C

NM_000203.4:c.385+1G>C

NR_110313.1:n.473+1G>C

NM_001363576.1:c.-12+1G>C

Pathogenic

PM2_Supporting PM3 PP4_Moderate PS1_Supporting PVS1

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:c.385+1G>C variant in IDUA occurs within the canonical splice donor site of intron 3. It is predicted to cause skipping of biologically-relevant-exon 3 out of 14 exons, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients from a Mexican cohort have been reported with "low or no activity of α-L-iduronidase" and treated with enzyme replacement therapy. One patient from Spain was reported with clinical features consistent with MPS1, elevated urine GAGs, and deficient IDUA activity, meeting three criteria for PP4 (PP4_Moderate). Both of the individuals from Mexico are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP - c.46_57del ((p.Ser16_Ala19del) (ClinVar variation ID: 92643) in one patient and c.1598C>G (p.Pro533Arg) (ClinVar variation ID: 11910) in the other patient. Phase was not confirmed in either patient (PMID: 25098213) (2 x 0.5 points = 1 point) (PM3). The patient from Spain is compound heterozygous for the variant and c.655G>C (p.Gy219Arg). The allelic data from this patient will be used in the classification of p.Gly219 Arg and is not included here to avoid circular logic. The variant is absent in gnomAD v4.1.0. (PM2_Supporting). Another variant at the same position, c.385+1G>A (ClinGen Allele Registry ID: CA355961228), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID: 37352859). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0: PVS1, PM3, PS1_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

PM2_Supporting

The variant is absent in gnomAD v4.1.0. (PM2_Supporting).

PM3

Two patients from a Mexican cohort have been reported. Both of them are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP - c.46_57del ((p.Ser16_Ala19del) (ClinVar variation ID: 92643) in one patient and c.1598C>G (p.Pro533Arg) (ClinVar variation ID: 11910) in the other patient. Phase was not confirmed in either patient (PMID: 25098213) (2 x 0.5 points = 1 point) (PM3). The patient from Spain is compound heterozygous for the variant and c.655G>C (p.Gy219Arg). The allelic data form this patient will be used in the classification of p.Gly219 Arg and is not included here to avoid circular logic.

PP4_Moderate

One patients from Spain was reported with clinical features consistent with MPS1, elevated urine GAGs, and deficient IDUA activity, meeting three criteria for PP4 (PP4_Moderate). Two patients from a Mexican cohort with MPS 1 were reported to have "low or no activity of α-L-iduronidase" and were treated with enzyme replacement therapy. While the data are consistent with a diagnosis of MPS I, there is insufficient data to apply PP4 for those two patients.

PS1_Supporting

Another variant at the same position, c.385+1G>A (ClinGen Allele Registry ID: CA355961228), has been classified as pathogenic by the ClinGen LD VCEP (PS1_Supporting, PMID: 37352859).

PVS1

Curation History

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