ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.386-2A>G (rs777295041)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000208607 SCV000752529 pathogenic Mucopolysaccharidosis type 1 2020-10-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the IDUA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs777295041, ExAC 0.009%). This variant has been reported in combination with another IDUA variant in individuals affected with mucopolysaccharidosis type I (PMID: 8019563, 11735025, 23837464, 24368159). This variant is also known as c.474-2 a>g and Int3-2a>g in the literature. ClinVar contains an entry for this variant (Variation ID: 222994). Experimental studies have shown that this splice acceptor change causes skipping of exon 4 (PMID: 8019563). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000666721 SCV000791067 pathogenic Hurler syndrome 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208607 SCV000917538 pathogenic Mucopolysaccharidosis type 1 2018-05-24 criteria provided, single submitter clinical testing Variant summary: IDUA c.386-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 245660 control chromosomes (gnomAD). The variant, c.386-2A>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh 2017, Beesley 2001), and most of the cases presented with a severe disease phenotype (Hurler syndrome). These data indicate that the variant is very likely to be associated with disease. Two publications reported no enzyme activity associated with this variant (Ghosh 2017, Bunge 1998). ClinVar has one entry for this variant after 2014 with a classification of "pathogenic". Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001550709 SCV001771084 pathogenic not provided 2020-06-19 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31194252, 24368159, 15300847, 28752568, 23837464, 8019563, 25525159, 21480867, 11735025, 9748610)
GeneReviews RCV000208607 SCV000264379 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208607 SCV001422945 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The c.386-2A>G variant in IDUA (also known as c.474-2A>G due to a difference in cDNA numbering) has been reported in at least 6 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 24368159, 11735025, 8019563) and has been identified in 0.008% (9/112774) of European (non-Finnish) chromosomes. 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: 222994) as pathogenic by Invitae, Counsyl, and GeneReviews. Functional studies demonstrating that the variant causes exon skipping provide some evidence that the c.386-2A>G variant may slightly impact protein function (PMID: 8019563). However, these types of assays may not accurately represent biological function. 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 4 reported pathogenic variants in individuals with MPS increases the likelihood that the c.386-2A>G variant is pathogenic (PMID: 24368159, 11735025, 8019563). The phenotype of an individual heterozygous for this variant is highly specific for MPS based on undetectable iduronidase activity, consistent with disease (PMID: 28752568). In summary, this variant meets criteria to be classified as pathogenic for IDUA in an autosomal recessive manner based on the prediction that it causes loss of function of the IDUA gene, the presence of the variant in combination with other pathogenic variants in affected individuals, and functional studies. ACMG/AMP Criteria applied: PM3_strong, PM2, PVS1_moderate, PS3_supporting, PP4 (Richards 2015).

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