Submissions for variant NM_000203.5(IDUA):c.613_617dup (p.Glu207fs)

dbSNP: rs786200915

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000012696	SCV000795133	pathogenic	Hurler syndrome	2017-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208610	SCV000917540	pathogenic	Mucopolysaccharidosis type 1	2018-06-22	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.613_617dupTGCTC (p.Glu207AlafsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.8e-06 in 227460 control chromosomes (gnomAD). The variant, c.613_617dupTGCTC, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh_2017, Kwak_2016, Yamagishi_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kwak_2016). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000208610	SCV001376850	pathogenic	Mucopolysaccharidosis type 1	2023-07-31	criteria provided, single submitter	clinical testing	This variant is also known as 704ins5. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11921). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8664897, 27520059, 29620724). This variant is present in population databases (rs786200915, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu207Alafs*29) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208610	SCV001422944	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The p.Glu207AlafsTer29 variant in IDUA has been reported in least 7 individuals with mucopolysaccharidosis (MPS) (PMID: 8664897, 27520059) and has been identified in 0.011% (2/17752) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786200915). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 207 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated 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 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with MPS increases the likelihood that the p.Glu207AlafsTer29 variant is pathogenic (VariationID: 11922; PMID: 8664897). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function and the presence of the variant in combination with known pathogenic variants in individuals with MPS. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015).
OMIM	RCV000012696	SCV000032931	pathogenic	Hurler syndrome	2004-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000208610	SCV000264388	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Common pathogenic variant in Japan
Natera, Inc.	RCV000208610	SCV002075301	pathogenic	Mucopolysaccharidosis type 1	2020-12-10	no assertion criteria provided	clinical testing