Variant: NM_000203.5(IDUA):c.494-1G>A

CA355961634

557942 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 3e5c1476-1085-4d57-b249-dd0bbb2923b9

Approved on: 2024-12-05

Published on: 2025-03-19

HGVS expressions

NM_000203.5:c.494-1G>A
NM_000203.5(IDUA):c.494-1G>A
NC_000004.12:g.1001467G>A
CM000666.2:g.1001467G>A
NC_000004.11:g.995255G>A
CM000666.1:g.995255G>A
NC_000004.10:g.985255G>A
NG_008103.1:g.19471G>A
ENST00000247933.9:c.494-1G>A
ENST00000514224.2:c.494-1G>A
ENST00000652070.1:n.550-1G>A
ENST00000247933.8:c.494-1G>A
ENST00000502910.5:c.353-1G>A
ENST00000504568.5:c.454-1G>A
ENST00000509948.5:c.287-1G>A
ENST00000514192.5:c.311-1G>A
ENST00000514224.1:c.98-1G>A
ENST00000514698.5:n.394-1G>A
NM_000203.4:c.494-1G>A
NR_110313.1:n.582-1G>A
NM_001363576.1:c.98-1G>A

Likely Pathogenic

• Met criteria codes: PVS1_Strong PM2_Supporting PM3

• Not Met criteria codes: PP4 PS1

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.494-1G>A variant in IDUA is a canonical splice acceptor variant. This variant is predicted to cause either an in-frame deletion of exon 5 including Glu182 (PVS1), or an activation of a cryptic splice site, leading to a frameshift and premature truncation (p.Arg166ThrfsTer27) (PVS1). The available experimental data do not definitively confirm either of these outcomes, and hence the decision has been made by the ClinGen IDUA VCEP to downgrade the strength of this criterion to PVS1_Strong. The highest population minor allele frequency in gnomAD v4.1.0. is 8.477e-7 (1/1179702 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). This variant has been reported primarily in Turkish patients, with at least five instances in the literature: four times in a homozygous genotype (PM3), and once as part of a compound heterozygous genotype with a variant (c.826G>A) that could be considered likely pathogenic (PMID: 21394825). Segregation studies for these patients were not available in this paper. There is a report of the variant in ClinVar (Variation ID: 557942). In summary, this variant meets the criteria to be classified as likely pathogenic 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): PVS1_Strong, PM2_Supporting, PM3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024)

Met criteria codes

• PVS1_Strong: The NM_000203.5:c.494-1G>A variant in IDUA occurs within the canonical splice acceptor site of intron 4. It is predicted to cause skipping of biologically-relevant-exon 5 out of 14. Loss of exon 5 is predicted to be an in-frame deletion, but this would include elimination of the key Glutamate-182 residue, which forms part of the active site. Loss of Glutamate-182 as a result of this variant does not appear to have been proven experimentally. However, RT-PCR analysis has been reported (PMID: 21394825) indicating an alternate 3' splice site (four nucleotides downstream), activating within exon 5, which will alter the open reading frame and introduce a premature stop codon (p.Arg166ThrfsTer27). Loss-of-function of IDUA is an established mechanism of disease (PMIDs 21480867, 11735025). However, the primary data demonstrating the RT-PCR result is not presented, and there is mention in the paper of 'predicted effect on protein' rather than RT-PCR-proven effects. Hence, this variant is predicted to cause either an in-frame deletion of exon 5 including Glu182 (PVS1), or an activation of a cryptic splice site, leading to a frameshift and premature truncation (p.Arg166ThrfsTer27) (PVS1). The available experimental data do not definitively confirm either of these outcomes, and hence the decision has been made by the ClinGen IDUA VCEP to downgrade the strength of this criterion to PVS1_Strong. Given some of the uncertainty regarding the experimental studies, in discussion with the broader ClinGen IDUA VCEP, the decision has been made to downgrade the strength of this criterion to PVS1_Strong.
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0. is 8.477e-7 (1/1179702 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 distinct probands with MPS I: the four homozygotes score 1 point in total, and the one compound heterozygote patient scores 0 points (see below). Of those individuals, one was compound heterozygous for the variant and c.826G>A (p.Glu276Lys). The c.826G>A variant could be considered likely pathogenic (see classification - PS3_Supporting, PM2_Supporting, PM3, PP3_Moderate, PP4), though it has not been formally classified in ClinVar or by the ClinGen consortium to-date. We will elect not to utilize this compound heterozygous case to contribute to PM3 for this c.494-1G>A variant. Four other individuals were homozygous for the variant (PMID: 21394825). Three Turkish patients homozygous for the variant are also reported by Atceken et al. (PMID: 27511503), but it is unclear whether these are the same patients or not. The total number of points is therefore 1, allowing for application of PM3 at moderate strength.

Not Met criteria codes

• PP4: All probands identified by Bertola et al. (2011) had deficient IDUA activity in either leukocytes or fibroblasts, though exact values were not provided (0.5 points). These cases did not meet any of the other specificity criteria for applying PP4: hence this criterion was not met.
• PS1: There is another canonical splice variant, c.494-1G>C (Variation ID: 197644) which has not been classified by ClinVar, but is likely to be assessed as likely pathogenic (PVS1, PM2_Supporting, PP3). SpliceAI suggests that a cryptic splice acceptor gain will occur 5bp downstream of the canonical -1 position: hence this variant is also predicted to result in a subsequent frameshift. Based on Walker et al. (PMID: 37352859) however, since the baseline predictive code is PVS1, the comparison variant is in the same dinucleotide acceptor and the comparison variant is judged as likely pathogenic, PS1 should not be applied.