Variant: NM_000203.5(IDUA):c.928C>T (p.Gln310Ter)

CA256115

11915 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: e13bf9ee-635b-49c8-8cd5-32fc2ae949ef

Approved on: 2025-03-03

Published on: 2025-03-12

HGVS expressions

NM_000203.5:c.928C>T
NM_000203.5(IDUA):c.928C>T (p.Gln310Ter)
NC_000004.12:g.1002117C>T
CM000666.2:g.1002117C>T
NC_000004.11:g.995905C>T
CM000666.1:g.995905C>T
NC_000004.10:g.985905C>T
NG_008103.1:g.20121C>T
ENST00000247933.9:c.928C>T
ENST00000514224.2:c.928C>T
ENST00000652070.1:n.984C>T
ENST00000247933.8:c.928C>T
ENST00000514224.1:c.532C>T
ENST00000514698.5:n.928C>T
NM_000203.4:c.928C>T
NR_110313.1:n.1016C>T
NM_001363576.1:c.532C>T

Likely Pathogenic

• Met criteria codes: PVS1_Strong PP4 PM2_Supporting PM3_Supporting

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.928C>T (p.Gln310Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR product showed a "doublet" with an upper band slightly larger than the normal band (505bp). Part of the mRNA was spliced from intron 5 to include 28nt of intronic sequence, indicating use of a cryptic splice site. This alternative splicing was said to create a frameshift and an open reading frame until exon 9. Since RT-PCR appears to show a near complete proportion of alternatively spliced transcript, the strength of PVS1 was reduced by 1 level to strong (PVS1_Strong; PMID: 8328452). This variant has been detected in at least 1 individual with MPS I. This individual was homozygous for the variant (PMID: 8328452; PM3_Supporting). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex, corneal opacities, hepatosplenomegaly, and arthropathy (PMID: 8328452; PP4). The highest population minor allele frequency in gnomAD v4.0. is 0.0000008630 (1/1158762 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). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 11915, 0 star review status) with 1 submitter classifying the variant as pathogenic; however this submitter is OMIM. In summary, this variant meets the criteria to be classified as likely 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_Strong, PM3_Supporting, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 3, 2025)

Met criteria codes

• PVS1_Strong: The NM_000203.5:c.928C>T (p.Gln310Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. RT-PCR product showed a "doublet" with an upper band slightly larger than the normal band (505bp). Part of the mRNA was spliced from intron 5 to include 28nt of intronic sequence, indicating use of a cryptic splice site. This alternative splicing was said to create a frameshift and an open reading frame until exon 9. Since RT-PCR appears to show a near complete proportion of alternatively spliced transcript, the strength of PVS1 was reduced by 1 level to strong (PVS1_Strong; PMID: 8328452).
• PP4: At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex, corneal opacities, hepatosplenomegaly, and arthropathy (PMID: 8328452; PP4). Per VCEP expert discussion, this proband was reported by a reputable group and, although our specific PP4 criteria are not explicitly met, PP4 will be applied to this variant.
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.0. is 0.0000008630 (1/1158762 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_Supporting: This variant has been detected in at least 1 individual with MPS I. This individual was homozygous for the variant (PM3= 0.5 points, PMID: 8328452; PM3_Supporting).