Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000631454 | SCV000752533 | pathogenic | Mucopolysaccharidosis type 1 | 2023-03-08 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 1 of the IDUA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 526835). Disruption of this splice site has been observed in individual(s) with Hurler syndrome (PMID: 28752568; Invitae). |
Broad Institute Rare Disease Group, |
RCV000631454 | SCV001422949 | pathogenic | Mucopolysaccharidosis type 1 | 2020-01-13 | criteria provided, single submitter | curation | The c.158+1G>A variant in IDUA has been reported in 1 individual with mucopolysaccharidosis (MPS) (PMID: 2872568) and has been identified in 0.002% (1/41250) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1264013707). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 526835) as likely pathogenic by Invitae. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS.The presence of this variant in combination with a reported pathogenic variant and in an individual with MPS increases the likelihood that the c.158+1G>A variant is pathogenic (VariationID: 11908; PMID: 2872568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function, its low frequency in the general population, and the presence of the variant in combination with another pathogenic variant in an individual with MPS. ACMG/AMP Criteria applied: PVS1, PM2, PM3_supporting (Richards 2015). |