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.1861C>G (p.Arg621Gly)

Curation History

CA2802458

444626 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9bf4aca6-06e1-4b38-b17a-ee559bd92791

Approved on: 2024-12-06

Published on: 2024-12-06

HGVS expressions

NM_000203.5:c.1861C>G

NM_000203.5(IDUA):c.1861C>G (p.Arg621Gly)

NC_000004.12:g.1004292C>G

CM000666.2:g.1004292C>G

NC_000004.11:g.998080C>G

CM000666.1:g.998080C>G

NC_000004.10:g.988080C>G

NG_008103.1:g.22296C>G

ENST00000247933.9:c.1861C>G

ENST00000514224.2:c.1861C>G

ENST00000652070.1:n.1917C>G

ENST00000247933.8:c.1861C>G

ENST00000514224.1:c.1465C>G

ENST00000514698.5:n.1972C>G

NM_000203.4:c.1861C>G

NR_110313.1:n.1953C>G

NM_001363576.1:c.1465C>G

Uncertain Significance

PP3 PM2

BA1 BS1 PP4 PM5 PM3

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.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance 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): PM2 Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024).

PP3

The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3).

PM2

This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4 is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

PMID: 35141277. This variant has been described in one individual, however, after personal communication with the author, they confirmed the typographical error, thus this publication can not count toward PP4.

PM5

c.1862G>C (p.Arg621Pro) is VUS: REVEL=0.6 1 homozygous proband was reported. PM3_Supporting (Patient #4 is homozygous for c.1862G>C (p.Arg621Pro) (PMID: 34833038) 1 point). c.1862G>T (p.Arg621Leu) is also VUS: REVEL= 0.68 1 proband with p.Arg621Leu in -trans with a pathogenic variant with W402X, but No c. confirmed in the paper, but can be c.1205G>A [CA220498] [PMID: 27896125] -OR- c.1206G>A. Both W402Ter are PVS1, and Pathogenic in ClinVar.

PM3

Curation History

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