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.386-2A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA356991

222994 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 92333c75-8f79-453e-87fc-99acbf52dd09

Approved on: 2024-12-06

Published on: 2024-12-15

HGVS expressions

NM_000203.5:c.386-2A>G

NM_000203.5(IDUA):c.386-2A>G

NC_000004.12:g.1000880A>G

CM000666.2:g.1000880A>G

NC_000004.11:g.994668A>G

CM000666.1:g.994668A>G

NC_000004.10:g.984668A>G

NG_008103.1:g.18884A>G

ENST00000247933.9:c.386-2A>G

ENST00000514224.2:c.386-2A>G

ENST00000652070.1:n.442-2A>G

ENST00000247933.8:c.386-2A>G

ENST00000502910.5:c.245-2A>G

ENST00000504568.5:c.346-2A>G

ENST00000506561.5:n.395-2A>G

ENST00000508168.5:n.264-2A>G

ENST00000509948.5:c.179-2A>G

ENST00000514192.5:c.203-2A>G

ENST00000514224.1:c.-11-2A>G

ENST00000514698.5:n.286-2A>G

NM_000203.4:c.386-2A>G

NR_110313.1:n.474-2A>G

NM_001363576.1:c.-11-2A>G

Pathogenic

PP4 PM3_Very Strong PM2_Supporting PVS1_Moderate

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.386-2A>G variant in IDUA, reported in older literature as 474-2A>G, occurs within the canonical splice acceptor site of intron 3. RT-PCR studies revealed that this variant results in skipping of exon 4 (PMID: 8019563). This is expected to result in an in-frame deletion of 36 amino acids which represents <10% of the protein. The in silico predictor SpliceAI does not predict the use of a cryptic splice site nearby (PVS1_Moderate). The variant has been identified in more than 20 individuals who have been diagnosed with MPS1, including 3 individuals with documented laboratory values showing deficiency of IDUA activity, two of who also have elevated urine GAGs (PMIDs: 23430808, 23837464) (PP4). Of these individuals at least 17 are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP including c.1205G>A, p.Trp402Ter (at least 10 individuals) (PMIDs: 8019563, 28752568), c.1855C>T (p.Arg619Ter) (PMID: 11735025), p.Pro533Arg (PMID: 8019563), c.208C>T (p.Gln70Ter) (at least 2 individuals) (PMIDs: 23430808, 28752568), and c.540_544delGAATG (p.Trp180Ter) (PMID: 28752568), and at least two are homozygous for the variant homozygotes (PMID: 28752568, 31194252) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and either c.236C>T (p.Ala79Val) (PMID: 28752568), c.653T>C (p.Leu218Pro) (PMID: 28752568), c.41T>G (p.Leu14Arg) (PMID: 28752568), p.Arg383His (PMID: 23837464) or p.Leu238Gln (PMID: 24368159); The allelic data from these patients will be used in the classifications of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0.is 0.0002086 (249/1179062 alleles; no homozygotes) 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: 222994). In summary, this variant meets the criteria to be classified as pathogenic for MPS1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PVS1_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

PP4

This variant has been identified in more than 20 individuals who have been diagnosed with MPS1, including 3 individuals with documented laboratory values showing deficiency of IDUA activity, two of who also have elevated urine GAGs (PMIDs: 23430808, 23837464) (PP4).

PM3_Very Strong

Of these individuals at least 17 are compound heterozygous for the variant and a variant that has been classified as pathogenic by the ClinGen LD VCEP including c.1205G>A, p.Trp402Ter (at least 10 individuals, maximum 2 x 0.5 points) (PMIDs: 8019563, 28752568), c.1855C>T (p.Arg619Ter) (0.5 points) (PMID: 11735025), p.Pro533Arg (0.5 points) (PMID: 8019563), c.208C>T (p.Gln70Ter) (at least 2 individuals, maximum 2x 0.5) (PMIDs: 23430808, 28752568), and c.540_544delGAATG (p.Trp180Ter) (0.5 points) (PMID: 28752568), and at least two are homozygous for the variant homozygotes (PMID: 28752568, 31194252) (maximum 2 x 0.5 points). Total 4.5 points (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and either c.236C>T (p.Ala79Val) (PMID: 28752568), c.653T>C (p.Leu218Pro) (PMID: 28752568), c.41T>G (p.Leu14Arg) (PMID: 28752568), p.Arg383His (PMID: 23837464) or p.Leu238Gln (PMID: 24368159); The allelic data from these patients will be used in the classifications of the missense variants and is not included here to avoid circular logic.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0.is 0.0002086 (249/1179062 alleles; no homozygotes) 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).

PVS1_Moderate

The NM_000203.5:c.386-2A>G variant in IDUA occurs within the canonical splice acceptor site of intron 3. RT-PCR studies revealed that this variant results in skipping of exon 4 (PMID: 8019563). This is expected to result in an in-frame deletion of 36 amino acids which represents <10% of the protein. In silico predictor SpliceAI does not predict the use of a cryptic splice site nearby (PVS1_Moderate).

Curation History

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