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.1091C>A (p.Thr364Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA355963315

2961353 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 846711c8-7efb-4e7f-9f8e-1549f6b8f316

Approved on: 2024-12-05

Published on: 2025-03-20

HGVS expressions

NM_000203.5:c.1091C>A

NM_000203.5(IDUA):c.1091C>A (p.Thr364Lys)

NC_000004.12:g.1002387C>A

CM000666.2:g.1002387C>A

NC_000004.11:g.996175C>A

CM000666.1:g.996175C>A

NC_000004.10:g.986175C>A

NG_008103.1:g.20391C>A

ENST00000247933.9:c.1091C>A

ENST00000514224.2:c.1091C>A

ENST00000652070.1:n.1147C>A

ENST00000247933.8:c.1091C>A

ENST00000514224.1:c.695C>A

ENST00000514698.5:n.1198C>A

NM_000203.4:c.1091C>A

NR_110313.1:n.1179C>A

NM_001363576.1:c.695C>A

Uncertain Significance

PP3_Moderate PM2_Supporting PM5

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.1091C>A variant in IDUA is a missense variant predicted to cause substitution of threonine by lysine at amino acid 364 (p.Thr364Lys). To our knowledge, this variant has not been reported in the literature in any individuals with MPS I, and no results of functional assays are available. This variant is absent in gnomAD v4.1.0.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898 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). Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5). In summary, this variant meets the criteria to be classified as a VUS 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): PM2_Supporting, PP3_Moderate, PM5. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

PP3_Moderate

The computational predictor REVEL gives a score of 0.898 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).

PM2_Supporting

This variant is absent in gnomAD v4.0. (PM2_Supporting).

PM5

Another missense variant c.1091C>T (p.Thr364Met) (ClinVar Variation ID: 11925) in the same codon has been classified as pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP (PM5).

Curation History

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