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_001363576.1:c.430G>A

CA355962355

3233261 (ClinVar)

Gene: IDUA (HGNC:3425)

Condition: mucopolysaccharidosis type 1 (MONDO:0001586)

Inheritance Mode: Autosomal recessive inheritance

UUID: 4d0d306d-ad40-4e0f-8278-e402d15ad508

Approved on: 2025-05-23

Published on: 2025-05-23

HGVS expressions

NM_001363576.1:c.430G>A

NC_000004.12:g.1002015G>A

CM000666.2:g.1002015G>A

NC_000004.11:g.995803G>A

CM000666.1:g.995803G>A

NC_000004.10:g.985803G>A

NG_008103.1:g.20019G>A

ENST00000247933.9:c.826G>A

ENST00000514224.2:c.826G>A

ENST00000652070.1:n.882G>A

ENST00000247933.8:c.826G>A

ENST00000514192.5:c.643G>A

ENST00000514224.1:c.430G>A

ENST00000514698.5:n.826G>A

NM_000203.4:c.826G>A

NR_110313.1:n.914G>A

NM_000203.5:c.826G>A

Likely Pathogenic

PS3_Supporting PP3_Moderate PP4 PM2_Supporting PM3

BP2 BP3 BP5 BP7 BS4 PP1 PS2 PS1 PM1 PM5 PM6

Evidence Links 1

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.826G>A in IDUA is a missense variant resulting in the substitution of glutamate by lysine at amino acid 276 (p.Glu276Lys). This variant has been reported in at least five probands with MPS I, all with a milder phenotype. In one patient homozygous for this genetic change (PMID 21364962), a highly-specific combination of clinical and biochemical evidence for MPS I has been reported (PMID: 21364962) (PP4). All other probands are also reported to have a confirmed enzymatic diagnosis. This variant has been detected in at least five probands with MPS I in the available literature. There is at least one homozygous patient of Thai ancestry (PMID 21364962), and three Turkish siblings (reported in PMID 23786846, but potentially the same proband as in PMID 21394825), scoring 1 point in total (max for homozygous individuals). Two individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic for MPS I including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (P by LD VCEP, phase unconfirmed, 0.5 points) (PMID: 35141277), and c.494-1G>A (ClinVar Variation ID: 557942) (LP by LD VCEP, phase unconfirmed, 0.25 points) (PMID: 21394825). Another individual is compound heterozygous for the variant and c.250G>C (p.Gly84Arg). The allelic data from the latter patient will be used in the classification of p.Gly84Arg and is not included here to avoid circular logic. Total 1.75 points (PM3). Experimental evidence from a COS-7 cell line, with c.826G>A expressed through site-directed mutagenesis, demonstrated minimal residual enzyme activity (approximately 1%) (PMID 21364962) (PS3_Supporting). The computational predictor REVEL gives a score of 0.833 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). The highest population minor allele frequency in gnomAD v4.1.0. is 8.522e-7 (1/1173452 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). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PM3, PP3_Moderate, PP4, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 23, 2025).

PS3_Supporting

Prommajan et al. (2011) transiently transfected the c.826G>A variant into COS-7 cells. The experiment was performed twice in triplicate, included a positive and negative control and accounted for the background IDUA activity in COS-7 cells, though there was no evidence that sequencing was used to confirm that the engineered mutation was present in the COS-7 cells after site-directed mutagenesis. Once the background enzyme activity is subtracted out, the residual enzyme activity is around 1%. Overall this appears to meet criteria in itself to apply PS3_Supporting.

PP3_Moderate

The computational predictor REVEL gives a score of 0.833 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).

PP4

Patient 2 from PMID 21364962 has two (claw hand deformity i.e. arthropathy and corneal opacity) specific clinical features of MPS (one criterion met). They also have alpha-L-iduronidase enzyme activity that is well outside the normal range (0.61 nmol/h/mg protein; mean and SD in controls of 23.10±8.80 nmol/h/mg protein)(second criterion met). Since two criteria are met, PP4 can be applied at its standard strength.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 8.522e-7 (1/1173452 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

This variant has been detected in at least five probands with MPS I in the available literature. There is at least one homozygous patient of Thai ancestry (PMID 21364962), and three Turkish siblings (reported in PMID 23786846, but potentially the same proband as in PMID 21394825), scoring 1 point in total (max for homozygous individuals). Two individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic for MPS I including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (P by LD VCEP, phase unconfirmed, 0.5 points) (PMID: 35141277), and c.494-1G>A (ClinVar Variation ID: 557942) (LP by LD VCEP, phase unconfirmed, 0.25 points) (PMID: 21394825). Another individual is compound heterozygous for the variant and c.250G>C (p.Gly84Arg). The allelic data from the latter patient will be used in the classification of p.Gly84Arg and is not included here to avoid circular logic. Total 1.75 points (PM3)

BP2

This variant has not been reported to be in cis with a pathogenic variant in any patients with MPS I.

BP3

This is a missense variant: this criterion does not apply.

BP5

There is no known alternate molecular basis for deficiency of alpha-L-iduronidase activity, other than variants in IDUA.

BP7

This is a missense variant: this criterion does not apply.

BS4

Lack of familial segregation has not been reported for this variant.

PP1

Co-segregation in multiple affected family members has not been reported for this variant.

PS2

This variant has not been reported as a de novo change.

PS1

No other established pathogenic variants are reported with the same amino acid change.

PM1

This variant does not involve one of the specific residues known to be crucial to the function of IDUA.

PM5

No pathogenic/likely pathogenic missense changes have been reported at this amino acid residue. There are two reports of the missense change c.828G>C causing p.(Glu276Asp), both of which have classified this variant as a variant of uncertain significance.

PM6

This variant has not been reported as a de novo change.

Curation History

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