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

gnomAD frequency: 0.00001  dbSNP: rs777295041

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000208607	SCV005619878	pathogenic	Mucopolysaccharidosis type 1	2024-12-06	reviewed by expert panel	curation	The NM_000203.5:c.386-2A>G variant in IDUA, reported in older literature as 474-2A>G, occurs within the canonical splice acceptor site of intron 3. RT-PCR studies revealed that this variant results in skipping of exon 4 (PMID: 8019563). This is expected to result in an in-frame deletion of 36 amino acids which represents <10% of the protein. The in silico predictor SpliceAI does not predict the use of a cryptic splice site nearby (PVS1_Moderate). The variant has been identified in more than 20 individuals who have been diagnosed with MPS1, including 3 individuals with documented laboratory values showing deficiency of IDUA activity, two of who also have elevated urine GAGs (PMIDs: 23430808, 23837464) (PP4). Of these individuals at least 17 are compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP including c.1205G>A, p.Trp402Ter (at least 10 individuals) (PMIDs: 8019563, 28752568), c.1855C>T (p.Arg619Ter) (PMID: 11735025), p.Pro533Arg (PMID: 8019563), c.208C>T (p.Gln70Ter) (at least 2 individuals) (PMIDs: 23430808, 28752568), and c.540_544delGAATG (p.Trp180Ter) (PMID: 28752568), and at least two are homozygous for the variant homozygotes (PMID: 28752568, 31194252) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and either c.236C>T (p.Ala79Val) (PMID: 28752568), c.653T>C (p.Leu218Pro) (PMID: 28752568), c.41T>G (p.Leu14Arg) (PMID: 28752568), p.Arg383His (PMID: 23837464) or p.Leu238Gln (PMID: 24368159); The allelic data from these patients will be used in the classifications of the missense variants and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0.is 0.0002086 (249/1179062 alleles; no homozygotes) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).There is a ClinVar entry for this variant (Variation ID: 222994). In summary, this variant meets the criteria to be classified as pathogenic for MPS1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PVS1_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000208607	SCV000752529	pathogenic	Mucopolysaccharidosis type 1	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the IDUA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs777295041, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type I (PMID: 8019563, 11735025, 23837464, 24368159). This variant is also known as c.474-2 a>g and Int3-2a>g. ClinVar contains an entry for this variant (Variation ID: 222994). Studies have shown that disruption of this splice site results in exon skipping, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 8019563). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208607	SCV001422945	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	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).
GeneDx	RCV001550709	SCV001771084	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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.; This variant is associated with the following publications: (PMID: 9748610, 11735025, 21480867, 25525159, 8019563, 23837464, 28752568, 15300847, 24368159, 31194252, 31589614)
Revvity Omics, Revvity	RCV001550709	SCV002023107	pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288837	SCV002581283	pathogenic	Mucopolysaccharidosis, MPS-I-H/S	2022-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031783	SCV005667749	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2024-03-29	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001550709	SCV001955872	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001550709	SCV001964571	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000208607	SCV002083101	pathogenic	Mucopolysaccharidosis type 1	2021-06-24	no assertion criteria provided	clinical testing