Variant: NM_000203.5(IDUA):c.613_617dup (p.Glu207fs)

CA256123

11921 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 5da672fe-07d8-438b-bb7c-408369ef445e

Approved on: 2024-12-05

Published on: 2025-03-19

HGVS expressions

NM_000203.5(IDUA):c.613_617dup
NM_000203.5:c.613_617dup
NM_000203.5(IDUA):c.613_617dup (p.Glu207fs)
NC_000004.12:g.1001702_1001706dup
CM000666.2:g.1001702_1001706dup
NC_000004.11:g.995490_995494dup
CM000666.1:g.995490_995494dup
NC_000004.10:g.985490_985494dup
NG_008103.1:g.19706_19710dup
ENST00000247933.9:c.613_617dup
ENST00000514224.2:c.613_617dup
ENST00000652070.1:n.669_673dup
ENST00000247933.8:c.613_617dup
ENST00000502910.5:c.472_476dup
ENST00000504568.5:c.573_577dup
ENST00000509948.5:c.406_410dup
ENST00000514192.5:c.430_434dup
ENST00000514224.1:c.217_221dup
ENST00000514698.5:n.513_517dup
NM_000203.4:c.613_617dup
NR_110313.1:n.701_705dup
NM_001363576.1:c.217_221dup

Pathogenic

• Met criteria codes: PM3 PM2_Supporting PVS1

• Not Met criteria codes: PP4

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000203.5:c.613_617dup (p.Glu207AlafsTer29) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 8 probands with a diagnosis of MPS I have been reported with the variant. At least 3 individuals with severe MPS I were homozygous for the variant (PMIDs: 8664897, 29620724; PM3). The allelic data for compound heterozygous individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002011 (9/44746 alleles) in the East Asian 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 pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

Met criteria codes

• PM3: This variant has been detected in at least 3 individuals with MPS I who were homozygous for the variant (PM3=1 point max; PMIDs: 8664897, 29620724; PM3). 6 additional probands have this variant in compound heterozygosity with another variant that has not yet been evaluated by the Lysosomal Diseases VCEP. Not scoring those cases to allow for the other variant to use the current variant for PM3, if needed, since the current is already at pathogenic.
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002011 (9/44746 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).
• PVS1: The NM_000203.5:c.613_617dup (p.Glu207AlafsTer29) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PP4: At least 8 probands with a diagnosis of MPS I have been reported with the variant but insufficient detail to apply PP4.