Submissions for variant NM_000203.5(IDUA):c.590-7G>A

dbSNP: rs762411583

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669065	SCV000793766	pathogenic	Hurler syndrome	2017-08-30	criteria provided, single submitter	clinical testing
Invitae	RCV000208601	SCV001232833	pathogenic	Mucopolysaccharidosis type 1	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with Scheie syndrome (PMID: 8213840, 28752568). This variant is also known as 678-7G>A. ClinVar contains an entry for this variant (Variation ID: 222996). Studies have shown that this variant results in activation of a cryptic splice acceptor and introduces a premature termination codon (PMID: 8318992). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208601	SCV001422678	pathogenic	Mucopolysaccharidosis type 1	2020-01-14	criteria provided, single submitter	curation	The c.590-7G>A variant in IDUA has been reported in at least 10 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 8213840, 9748610) and has been identified in 0.001% (1/106874) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762411583). 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: 222996) as pathogenic by Counsyl, OMIM, and GeneReviews. Functional studies demonstrating that the variant activates a cryptic splice site provide some evidence that the c.590-7G>A variant may slightly impact protein function (PMID: 8213840). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the 3' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is high' ly specific for MPS based on their Alpha-L-iduronidase protein levels being <1% consistent with disease (PMID: 9748610, 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with reported pathogenic variants, the phenotype of patients with the variant being highly specific for MPS, and evidence of aberrant splicing. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4, PS3_supporting (Richards 2015).
Revvity Omics, Revvity	RCV003137798	SCV003818266	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing
OMIM	RCV000012688	SCV000032923	pathogenic	Mucopolysaccharidosis, MPS-I-S	1993-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000208601	SCV000264381	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Variant causes attenuated MPS I; creates alternate splice site, but (as old splice site is not obliterated) some normal enzyme is produced.
Natera, Inc.	RCV000208601	SCV001461752	likely pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing