Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: IDUA vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000203.5(IDUA):c.590-7G>A

CA356990

222996 (ClinVar)

Gene: IDUA
Condition: mucopolysaccharidosis type 1
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: b97d1371-e9cc-45bc-9b2b-fb9084c93edc
Approved on: 2024-12-06
Published on: 2025-06-07

HGVS expressions

NM_000203.5:c.590-7G>A
NM_000203.5(IDUA):c.590-7G>A
NC_000004.12:g.1001672G>A
CM000666.2:g.1001672G>A
NC_000004.11:g.995460G>A
CM000666.1:g.995460G>A
NC_000004.10:g.985460G>A
NG_008103.1:g.19676G>A
ENST00000247933.9:c.590-7G>A
ENST00000514224.2:c.590-7G>A
ENST00000652070.1:n.646-7G>A
ENST00000247933.8:c.590-7G>A
ENST00000502910.5:c.449-7G>A
ENST00000504568.5:c.550-7G>A
ENST00000509948.5:c.383-7G>A
ENST00000514192.5:c.407-7G>A
ENST00000514224.1:c.194-7G>A
ENST00000514698.5:n.490-7G>A
NM_000203.4:c.590-7G>A
NR_110313.1:n.678-7G>A
NM_001363576.1:c.194-7G>A
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Pathogenic

Met criteria codes 4
PVS1_Strong PP4_Moderate PM2_Supporting PM3_Strong

Evidence Links 0

Expert Panel

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.590-7G>A variant in IDUA occurs within the splice acceptor site motif of intron 5. RT-PCR analysis revealed skipping of biologically-relevant-exon 6/14, or, rarely, intron 5 inclusion, resulting mainly in splicing at nt -28 of intron 5, and also a very small amount of normal IDUA mRNA (PMID: 8213840; 9748610) (PVS1_Strong (RNA)). This variant is also reported as IDUA:c. 678-7 G>A in older literature (PMID: 8213840). This variant has been detected in at least 10 individuals with MPS I, all compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, all phase unconfirmed, including c.208C>T (p.Gln70Ter) (PMID: 28752568, ClinVar Variation ID: 11909, 0.5 points), c.1205G>A (p.Trp402Ter) (PMID: 28752568, CinVar Variation ID: 11908, 7 patients, max 2 x 0.5 points), and (c.1029C>G (p.Tyr343Ter) (C;inVar Variation ID: 550474, clinical lab, 0.5 points) (PM3_Strong). Total 2 points (PM3_Strong). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, a significant reduction in urine GAGs upon treatment with enzyme replacement therapy, and clinical features specific to MPS I including arthropathy, corneal involvement, and valvular thickening. (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004241 (50/1178952 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 222996). 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): PVS1_strong, PM3_strong, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Met criteria codes
PVS1_Strong
The NM_000203.5: c.590-7G>A variant in IDUA occurs within the splice acceptor site motif of intron 5. RT-PCR analysis revealed skipping of biologically-relevant-exon 6/14, or, rarely, intron 5 inclusion, resulting mainly in splicing at nt -28 of intron 5, and also a very small amount of normal IDUA mRNA (PMID: 8213840; 9748610) (PVS1_Strong (RNA)).
PP4_Moderate
At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, a significant reduction in urine GAGs upon treatment with enzyme replacement therapy, and clinical features specific to MPS I including arthropathy, corneal involvement, and valvular thickening. (PP4_Moderate).
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004241 (50/1178952 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
PM3_Strong
This variant has been detected in at least 10 individuals with MPS I, all compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, all phase unconfirmed, including c.208C>T (p.Gln70Ter) (PMID: 28752568, ClinVar Variation ID: 11909, 0.5 points), c.1205G>A (p.Trp402Ter) (PMID: 28752568, CinVar Variation ID: 11908, 7 patients, max 2 x 0.5 points), and (c.1029C>G (p.Tyr343Ter) (C;inVar Variation ID: 550474, clinical lab, 0.5 points) (PM3_Strong). Total 2 points (PM3_Strong).
Curation History
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