Submissions for variant NM_000203.5(IDUA):c.1205G>A (p.Trp402Ter)

gnomAD frequency: 0.00086  dbSNP: rs121965019

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078374	SCV000232926	pathogenic	not provided	2016-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000078374	SCV000329822	pathogenic	not provided	2020-12-11	criteria provided, single submitter	clinical testing	One of the most common pathogenic variants identified in European and American individuals with mucopolysaccharidosis type I, accounting for 17-48% of pathogenic variants in these populations (Bunge et al., 1994; Beesley et al., 2001; Pollard et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32371413, 31980526, 32670797, 7951228, 30548430, 29654546, 1301196, 22976768, 26965916, 27511503, 15081804, 21364962, 8213840, 12509712, 8554071, 9427149, 11735025, 25525159, 19751987, 24368159, 23786846, 24698225, 30609409)
Illumina Laboratory Services, Illumina	RCV000384297	SCV000451787	pathogenic	Mucopolysaccharidosis type 1	2017-10-23	criteria provided, single submitter	clinical testing	The IDUA c.1205G>A (p.Trp402Ter) variant is a stop-gained variant and is well described in the literature as a pathogenic variant associated with mucopolysaccharidosis type I, accounting for 37% of disease alleles in Europeans, 43% in North Americans of European ancestry, and 55% of Australasians (Clarke et al. 2016). The p.Trp402Ter variant has been reported in at least seven studies in which it is found in a total of at least 30 individuals with mucopolysaccharidosis type I, including in 12 in a homozygous state, in at least 17 in a compound heterozygous state, and in one in a heterozygous state where a second variant was not identified. The variant was also found in an additional 93 of 298 disease alleles of unspecified zygosity (Scott et al. 1992; Beesley et al. 2001; Pollard et al. 2013; Oussoren et al. 2013; Ahmed et al. 2014; Leroux et al. 2014; Atceken et al. 2016). The p.Trp402Ter variant was absent from 20 control alleles but is reported at a frequency of 0.00045 in the combined European American and African American populations of the Exome Sequencing Project. Functional studies demonstrated that the variant resulted in low or undetectable IDUA activity in the homozygous state and 50% activity in the heterozygous state in human and mouse (Scott et al. 1992; Beesley et al. 2001; Wang et al. 2010; Oussoren et al. 2013; Leroux et al. 2014). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Trp402Ter variant is classified as pathogenic for mucopolysaccharidosis type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000012683	SCV000538044	pathogenic	Hurler syndrome	2016-01-27	criteria provided, single submitter	clinical testing	The c.1205G>A (p.Trp402ter) nonsense variant in the IDUA gene is the most common variant reported in individuals affected with Hurler Syndrome (Scott et al., 1992; Pollard et al., 2013; Leroux et al., 2014). The p.Trp402ter variant is predicted to cause a protein termination in exon 9 (out of a total of 14 exons in the coding sequence). Nonsense variants have been described in the IDUA gene in several affected individuals (Scott et al., 1992; Pollard et al., 2013) and are, therefore, a common mechanism of disease. Multiple in vivo functional studies have demonstrated the p.Trp402ter variant results in IDUA deficiency (Scott et al., 1992; Wang et al., 2009; Oussoren et al., 2013). This c.1205G>A variant has not been reported in the three population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.86; CADD = 41), and reputable diagnostic laboratories have reported this variant as pathogenic. IDUA is the only gene in which pathogenic variants are known to cause Hurler Syndrome. Therefore, this collective evidence supports the classification of the c.1205G>A (p.Trp402ter) as a Pathogenic variant for Hurler Syndrome.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000384297	SCV000627147	pathogenic	Mucopolysaccharidosis type 1	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp402*) 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). This variant is present in population databases (rs121965019, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 1301196, 11735025, 20301341, 21394825, 22976768). ClinVar contains an entry for this variant (Variation ID: 11908). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000384297	SCV000695969	pathogenic	Mucopolysaccharidosis type 1	2019-12-17	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1205G>A (p.Trp402X) 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 0.00059 in 90548 control chromosomes. c.1205G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 and is reported as one of the most common pathogenic variants causing Mucopolysaccharidosis type I. Clinical and functional data are consistent with the pathogenic outcome for the variant. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000384297	SCV000712125	pathogenic	Mucopolysaccharidosis type 1	2016-05-16	criteria provided, single submitter	clinical testing	The p.Trp402X variant in IDUA has been reported in several individuals with muco polysaccharidosis type I (MPS-I) and has been associated with the severe Hurler syndrome phenotype in the homozygous state (Scott 1992, Pollard 2013, Cobos 2015 , Ahmed 2014, Oussoren 2013, Leroux 2014). It was absent form large population s tudies. This nonsense variant leads to a premature termination codon at positio n 402, which is predicted to lead to a truncated or absent protein. In mouse mod els, this variant led to phenotypes associated with the disease (Wang 2010). In summary, the p.Trp402X variant meets our criteria to be classified as pathogenic for mucopolysaccharidosis type I in an autosomal recessive manner, based upon i ts identification with patients, predicted functional impact and animal model st udies.
Fulgent Genetics, Fulgent Genetics	RCV000477890	SCV000894345	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000384297	SCV000929875	pathogenic	Mucopolysaccharidosis type 1	2019-01-01	criteria provided, single submitter	literature only	PVS1: nonsense. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2: Very low frequency in GnomAD
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004934	SCV001164454	pathogenic	Mucopolysaccharidosis, MPS-I-H/S	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Trp402Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive Hurler-Scheie syndrome. This variant has also been reported pathogenic in ClinVar (Variation ID: 11908) and is a well-known pathogenic variant in individuals with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (86/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). In summary, this variant meets criteria to be classified as pathogenic for Hurler-Scheie syndrome in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in European individuals with Hurler Scheie syndrome. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).
Myriad Genetics, Inc.	RCV000012683	SCV001193947	pathogenic	Hurler syndrome	2019-11-12	criteria provided, single submitter	clinical testing	NM_000203.3(IDUA):c.1205G>A(W402*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 1301196, 21394825, 7951228 and 11735025. Classification of NM_000203.3(IDUA):c.1205G>A(W402*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000384297	SCV001422680	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The p.Trp402Ter variant in IDUA has been reported in at least 85 individuals with mucopolysaccharidosis (MSP) (PMID: 28752568, 10215409) and has been identified in 0.142% (69/48650) of European (non-Finnish) chromosomes, 0.046% (9/19442) of Latino chromosomes, and 0.034% (3/8772) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965019). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 11908) as pathogenic by 12 submitters. Animal models in mice have shown that this variant causes MSP (doi: 10.1016/j.ymgme.2014.12.026). This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the IDUA gene is an established disease mechanism in MSP. The phenotype of individuals compound heterozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 28752568). The presence of this variant in 38 affected homozygotes and in combination with reported pathogenic variants in at least 38 affected individuals increases the likelihood that the p.Trp402Ter variant is pathogenic (VariationID: 222996, 11909, 167190; PMID: 28752568, 10215409). In summary, this variant meets criteria to be classified as pathogenic for MSP in an autosomal recessive manner based on the prediction that it will cause loss of function, mouse models, and the presence of the variant in affected homozygotes. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015).
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000477890	SCV001423593	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2017-09-15	criteria provided, single submitter	clinical testing	[ACMG/AMP: PVS1, PS3, PS4_Moderate, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001004934	SCV001448767	pathogenic	Mucopolysaccharidosis, MPS-I-H/S	2016-07-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000078374	SCV001748089	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	IDUA: PM3:Very Strong, PVS1, PM2
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000078374	SCV002010071	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000078374	SCV002023115	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000477890	SCV002061789	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2021-12-29	criteria provided, single submitter	clinical testing	PVS1, PS3, PP1, PM3
Institute of Human Genetics, University Hospital Muenster	RCV002251896	SCV002506433	pathogenic	See cases	2023-07-04	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PP3,PP5
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251896	SCV002522896	pathogenic	See cases	2024-01-03	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2_supporting, PM3, PP4
Mayo Clinic Laboratories, Mayo Clinic	RCV000078374	SCV002525757	pathogenic	not provided	2021-09-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512986	SCV003559978	pathogenic	Inborn genetic diseases	2022-06-29	criteria provided, single submitter	clinical testing	The c.1205G>A (p.W402*) alteration, located in exon 9 (coding exon 9) of the IDUA gene, consists of a G to A substitution at nucleotide position 1205. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 402. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with a pathogenic IDUA mutation, in multiple individuals with mucopolysaccharidosis type I (MPS1) (Gort, 1998; Scott, 1992; Li, 2002; Bush, 2019; Guffon, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000012683	SCV005045018	pathogenic	Hurler syndrome	2024-02-13	criteria provided, single submitter	clinical testing	The IDUA c.1205G>A (p.Trp402Ter) variant is the most common reported variant in individuals affected with mucopolysaccharidosis I. This variant has been observed in both a homozygous and compound heterozygous state in affected individuals (Beesley CE et al., PMID: 11735025; Bertola F et al., PMID: 21394825; Gort L et al., PMID: 10215409; Pollard LM et al., PMID: 22976768; Scott HS et al., PMID: 1301196). This variant causes a stop gain, which is predicted to lead to nonsense mediated decay. In vivo mouse studies modeling this variant show no detectable alpha-L-iduronidase activity, indicating that this variant impacts protein function (Wang D et al., PMID: 19751987). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.14% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline pathogenic variant by ten submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
OMIM	RCV000012683	SCV000032918	pathogenic	Hurler syndrome	2001-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000384297	SCV000264385	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Common pathogenic variant in persons of European ancestry and Australasia
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477890	SCV000536710	pathogenic	Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S	2015-05-14	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078374	SCV001741205	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078374	SCV001973955	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000384297	SCV002075345	pathogenic	Mucopolysaccharidosis type 1	2020-10-05	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398488	SCV004110155	pathogenic	IDUA-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The IDUA c.1205G>A variant is predicted to result in premature protein termination (p.Trp402*). This variant has been repeatedly reported to be pathogenic for mucopolysaccharidosis type I (Scott et al. 1992. PubMed ID: 1301196; Pollard et al. 2013. PubMed ID: 22976768; Ahmed et al. 2014. PubMed ID: 24368159; Bush et al. 2019. PubMed ID: PMID: 29654546; Cospain et al. 2020. PubMed ID: 32670797). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in IDUA gene are expected to be pathogenic. In summary, we classify this variant as pathogenic.