4-1002945-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PM2_SupportingPP4PVS1_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1402+1G>A variant in IDUA occurs within the canonical splice donor site of intron 9. While the effect of this change has not been proven experimentally, it is predicted to cause skipping of biologically-relevant-exon 9 out of 14 total exons, resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been detected in at least two individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and c.502G>T p.(Gly168Ter), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID:33301762). The other individual was homozygous for the variant (PMID:27146977) (PM3). These two patients had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including coarse facies, hepatosplenomegaly, corneal opacity, recurrent infections, intellectual disability, hernia, and/or cardiomegaly, cardiomyopathy, and dysostosis multiplex (PP4)(PMIDs: 33301762, 27146977). This variant is absent in gnomAD v4.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555490). 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, PM3, PP4, PM2_Supporting).(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA355964379/MONDO:0001586/091
Frequency
Consequence
NM_000203.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1209636Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 586794
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 06, 2017 | - - |
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at