Submissions for variant NM_000203.5(IDUA):c.1174C>T (p.Leu392=)

gnomAD frequency: 0.01139  dbSNP: rs201682298

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000288834	SCV000451785	benign	Mucopolysaccharidosis type 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Eurofins Ntd Llc (ga)	RCV000591138	SCV000700304	benign	not specified	2017-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000591138	SCV000919537	benign	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1174C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 169258 control chromosomes in the gnomAD database, including 20 homozygotes. The observed variant frequency is approximately 4.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is benign. c.1174C>T has not been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1, on the other hand it was reported to be found in healthy controls and described as a polymorphism (Bertola 2011, Scott 1995). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; one of these laboratories classified the variant as benign, the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000288834	SCV001422671	benign	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The c.1174C>T (p.Leu392=) variant in IDUA has not been previously reported in individuals with mucopolysaccharidosis but has been identified in 1.964% (1347/68572) of European (non-Finnish) chromosomes, including 14 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201682298). This variant has also been reported in ClinVar (VariationID: 350229) as a VUS by Illumina Clinical Services Laboratory, likely benign by Mayo Clinical Testing Laboratories, and benign by EGL Genetic Diagnostics and Integrated Genetics. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on its frequency in the general population and multiple reports of unaffected homozygotes. ACMG/AMP Criteria applied: BS1, BS2, BP4, BP7 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000288834	SCV001640514	likely benign	Mucopolysaccharidosis type 1	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000675608	SCV001813364	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000675608	SCV005263630	likely benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000675608	SCV000801306	likely benign	not provided	2017-04-18	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000675608	SCV001739724	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000591138	SCV001926082	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000591138	SCV001956676	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000288834	SCV002075341	benign	Mucopolysaccharidosis type 1	2017-05-11	no assertion criteria provided	clinical testing