Variant: NM_000203.5(IDUA):c.1402+1G>T

CA355964387

1323099 (ClinVar)

Gene: IDUA

Condition: mucopolysaccharidosis type 1

Inheritance Mode: Autosomal recessive inheritance

UUID: 806636a3-52d4-4ec1-924e-4cb2696ec111

Approved on: 2024-12-06

Published on: 2024-12-15

HGVS expressions

NM_000203.5:c.1402+1G>T
NM_000203.5(IDUA):c.1402+1G>T
NC_000004.12:g.1002945G>T
CM000666.2:g.1002945G>T
NC_000004.11:g.996733G>T
CM000666.1:g.996733G>T
NC_000004.10:g.986733G>T
NG_008103.1:g.20949G>T
ENST00000247933.9:c.1402+1G>T
ENST00000514224.2:c.1402+1G>T
ENST00000652070.1:n.1458+1G>T
ENST00000247933.8:c.1402+1G>T
ENST00000502829.1:n.204+1G>T
ENST00000514224.1:c.1006+1G>T
ENST00000514698.5:n.1509+1G>T
NM_000203.4:c.1402+1G>T
NR_110313.1:n.1490+1G>T
NM_001363576.1:c.1006+1G>T

Likely Pathogenic

• Met criteria codes: PVS1_Strong PP4 PM3 PM2_Supporting

• Not Met criteria codes: 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.1402+1G>T variant in IDUA occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9 (there are 14 exons in IDUA), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been identified in three patients with clinical features of severe MPS 1 including including cognitive delay, visual impairment, joint disease, hepatosplenomegaly, hernia, cardiac disease, and/or respiratory disease. Two of these patients also had documented IDUA deficiency within the affected range in leukocytes (PMID: 21480867, 27896125). An additional patient was identified by newborn screening with confirmatory deficient IDUA, elevated urine GAGs, and was treated with ERT and HSCT (PMID: 37516270) (PP4). Of these individuals, two were homozygous for the variant (PMID: 21480867, 27896125), and one individual was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter), phase unknown (ClinVar Variation ID: 11908) (PMID: 37516270). Another individual is compound heterozygous for the variant and p.Ala79Val; the allelic data for this individual will be used in the classification of p.Ala79Val and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003924 (1/25482; 0 homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Additional variants at this splice donor site have been identified in individuals with features of MPS 1, including c.1402+1G>A (PMID: 27146977). There is a ClinVar entry for this variant (Variation ID: 1323099. 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 Storage Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_Strong, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

Met criteria codes

• PVS1_Strong: The NM_000203.5:c.1402+1G>T variant in IDUA occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9 (IDUA has 14 exons), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong).
• PP4: This variant has been identified in three patients with clinical features of severe MPS 1 including including cognitive delay, visual impairment, joint disease, hepatosplenomegaly, hernia, cardiac disease, and/or respiratory disease. Two of these patients also had documented IDUA deficiency within the affected range in leukocytes (PMID: 21480867, 27896125). An additional patient was identified by newborn screening with confirmatory deficient IDUA, elevated urine GAGs, and treated with ERT and HSCT (PMID: 37516270) (PP4).
• PM3: Two individuals with MPS I were homozygous for the variant (PMID: 21480867, 27896125; 2 x 0.5 points), and one individuals is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter), phase unknown (ClinVar Variation ID: 11908, 0.5 points) (PMID: 37516270). Another individual is compound heterozygous for the variant and p.Ala79Val; the allelic data for this individual will be used in the classification of p.Ala79Val and is not included here to avoid circular logic. Total points 1.5 (PM3).
• PM2_Supporting: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003924 (1/25482; 0 homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).

Not Met criteria codes

• PS1: Additional variants at this splice donor site have been identified in individuals with features of MPS 1, including c.1402+1G>A (PMID: 27146977). This variant has not yet been classified by the ClinGen LD VCEP.