NM_000203.5:c.208C>T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PM3PVS1
This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.208C>T (p.Gln70Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of a total of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. An immunochemical assay performed in fibroblast lines from two individuals homozygous for the variant and three individuals compound heterozygous for the variant and p.Trp402Ter found no detectable IDUA protein (PMID:1301941) (PVS1). This variant is the second most common variant identified in patients with mucopolysacchararidosis type 1 (MPS1), and is present mainly in Northern Europe, including Norway (54% of MPS1 alleles), Russia (42% of MPS1 alleles), Poland (30% of MPS1 alleles), and Austria (31% of MPS1 alleles) (Reviewed in PMID:29393969). At least 14 homozygotes (max 0.5 x 2 points = 1 point) and at least 45 individuals who are compound heterozygous for the variant and a second variant in IDUA, including another well-known pathogenic variant, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), have been reported (PMID:1301941, 7951228, 11735025, 28752568). The allelic data for many of these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, only 1 point was awarded here, the maximum points for homozygotes (PM3). Patients meeting two of the requirements for PP4, IDUA deficiency and elevated urine GAG levels have been reported (PMID:1301941) (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.002123 in the Finnish population, followed by 0.0005348 in the European non-Finnish population. This is higher than the Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.00025) and lower than the threshold for BS1 (>0.0025). Therefore, no population codes are met. More data is available in the literature but the classification of pathogenic has already been reached. There is a ClinVar entry for this variant (Variation ID: 11909). In summary, c.208C>T (p.Gln70Ter) is the second most frequent variant identified in patients with MPS1 and meets the criteria to be classified as pathogenic for this condition. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA204563/MONDO:0001586/091
Frequency
Consequence
NM_000203.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000578 AC: 88AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000472 AC: 115AN: 243460Hom.: 0 AF XY: 0.000513 AC XY: 68AN XY: 132634
GnomAD4 exome AF: 0.000481 AC: 703AN: 1460164Hom.: 0 Cov.: 30 AF XY: 0.000480 AC XY: 349AN XY: 726374
GnomAD4 genome 0.000578 AC: 88AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:11
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IDUA: PM3:Very Strong, PVS1, PM2 -
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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: 21831683, 30737479, 29654546, 7951228, 8401515, 24368159, 25525159, 22976768, 24314423, 1301941, 31133280, 23786846, 31980526, 31589614) -
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The IDUA p.Gln70X variant was identified in 69 of 500 proband chromosomes (frequency: 0.18) from individuals or families with Mucopolysaccharidosis type I (MPS I), and was not identified in 40 control chromosomes from healthy individuals (Beesley_2001_11735025, Scott_1992_1505961, Vazna_2009_19396826, Yogalingam_2004_15300847, Bunge_1994_7951228, Pollard_2013_22976768). This variant was also identified in the following databases: dbSNP (ID: rs121965020) as “with Pathogenic allele-”, ClinVar (10x as pathogenic by EGL Genetic, Laboratory for Molecular Medicine , Illumina , Counsyl, Gene Reviews, OMIM, Children's Hospital of Philadelphia), Clinvitae (6x as pathogenic by ClinVar, EmvClass) and LOVD 3.0 (31x). This variant was identified in The NHLBI GO Exome Sequencing Project in 10 of 8592 European American alleles, (freq. 0.001), the Exome Aggregation Consortium database (August 8th 2016) in 72 of 110236 chromosomes (freq. 0.00065), the genome Aggregation Database (beta, October 19th 2016) in 142 of 270128 chromosomes (freq. 0.0005) in the following populations: African in 4 of 23548 chromosomes (freq. 0.00017), European Non Finnish in 85 of 121110 chromosomes (freq. 0.0007) and Finnish in 53 of 25426 chromosomes (freq. 0.002), but was not seen in other, Latino, Ashkenazi Jewish, East Asian and South Asian populations. Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of a-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglycans dermatan sulfate and heparin sulfate (Yogalingam_2004_15300847). The IDUA gene is approximately 19 kb in length. It maps to chromosome 4p16.3 and contains 14 exons, producing a transcript of 2.3 kb in length, which encodes a precursor protein consisting of 653 amino acids (8). The first 27 amino acids of the protein represent a signal peptide. To date, 199 different disease-causing IDUA gene mutations have been reported (9) (http://www.hgmd.org), with variable distribution across populations. Among them, p.W402X, p.Q70X, p.P533R, and p.G51D are the most common mutations worldwide (Atceken_2016_27511503). The p.Gln208X variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the IDUA gene are an established mechanism of disease in autosomal recessive Mucopolysaccharidosis type I disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Mucopolysaccharidosis type 1 Pathogenic:7Other:1
The p.Gln70Ter variant has been reported in at least 22 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568) and has been identified in Identified in 0.194% (48/24766) of European (Finnish) chromosomes, 0.069% (85/122916) of European (non-Finnish) chromosomes, and 0.069% (4/14378) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP s121965020). 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: 11909) as pathogenic by 10 submitters. In vitro functional studies provide some evidence that the p.Gln70Ter variant may impact protein function (PMID: 11159948). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 70, 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 MPS. The presence of this variant in combination with a reported pathogenic variant and in 20 individuals with MPS increases the likelihood that the p.Gln70Ter variant is pathogenic (VariationID: 11908, 222996; PMID: 28752568). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on enzyme activity being less than 1% of normal consistent with disease (PMID: 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function, the presence of the variant in combination with other pathogenic variants, and functional studies. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015). -
Variant summary: The IDUA c.208C>T (p.Gln70X) variant results in a premature termination codon 584 amino acids from the end of the protein, predicted to cause a truncated or absent IDUA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp402X). The residual activity of IDUA was measured in fibroblast cell lines from a patient homozygous for Gln70X, showing that activity was essentially no activity, indicating that this is a null allele. One in silico tool predicts a damaging outcome for this variant. This variant was found in 72/110336 control chromosomes at a frequency of 0.0006526, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). However, the variant has been cited in many Hurler Syndrome (MPS IH, severe presentation) patients in both homozygous and compound heterozygous states. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
The p.Gln70X variant in IDUA has been reported in several individuals with Mucopolysaccharidosis type I (MPSI) in a homozygous or compound heterozygous state with another pathogenic variant, and is estimated to account for 10-15% of this disease in different European populations (Scott 1992, Clarke 1993, Gatti 1997, Gort 1997, Vazna 2009, Pollard 2013). The Gln70X variant led to reduced residual enzyme activity in functional studies (Oussoren 2013). This variant has also been identified in 0.3% (17/5282) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121965020), and in 0.1% (10/8592) of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This frequency is consistent with the estimated carrier frequency of MPSI (Moore 2008). This nonsense variant leads to a premature termination codon at position 70, which is predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in individuals with MPSI. In summary, this variant meets our criteria to be classified as pathogenic for MPSI in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM). -
The IDUA c.208C>T (p.Q70*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in individuals with MPS I (PMID: 1301941; 1505961; 8401515; 7951228; 9427149; 9787109; 10215409; 11735025; 19396826). -
The IDUA c.208C>T (p.Gln70Ter) variant is a stop gained variant that is well described in the literature as a common pathogenic variant for mucopolysaccharidosis type I, estimated to account for ten to thirty-five percent of disease alleles in different European populations. The variant is usually associated with a severe phenotype. In a sample of eight studies involving a total of 280 individuals, the p.Gln70Ter variant was found in 17 affected individuals in a homozygous state, 26 individuals in a compound heterozygous state, and in five individuals in a heterozygous state (Scott et al. 1992; Clarke et al. 1993; Bunge et al. 1994; Gort et al. 1998; Beesley et al. 2001; Vazna et al. 2009; Pollard et al. 2013; Oussoren et al. 2013). The variant was absent from 140 control alleles but is reported at a frequency of 0.00325 in the European (Finnish) population from the Exome Aggregation Consortium. Several studies reported that there was either no or very low residual enzyme activity in all individual samples (Scott et al. 1992; Vazna et al. 2009; Oussoren et al. 2013). Oussoren et al. (2013) demonstrated that individuals who were homozygous or compound heterozygous for the p.Gln70Ter variant showed residual IDUA activity of 0.1% and 0.2% of control activity, respectively. An immunochemical assay found no detectable protein in cell lines derived from individuals who were homozygous or compound heterozygous for the variant (Scott et al. 1992). Based on the collective evidence, the p.Gln70Ter 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. -
This sequence change creates a premature translational stop signal (p.Gln70*) 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 (rs121965020, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8401515, 21394825, 21831683, 22976768, 24314423, 24368159). ClinVar contains an entry for this variant (Variation ID: 11909). For these reasons, this variant has been classified as Pathogenic. -
Common variant in Europe and Russia; associated with severe MPS I -
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Hurler syndrome Pathogenic:4
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NM_000203.3(IDUA):c.208C>T(Q70*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 21394825, 19396826, 10215409 and 23786846. Classification of NM_000203.3(IDUA):c.208C>T(Q70*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). -
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Mucopolysaccharidosis, MPS-I-H/S Pathogenic:2
The heterozygous p.Gln70Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. The presence of this variant in combination with a likely pathogenic variant and in an individual with Hurler-Scheie syndrome increases the likelihood that the p.Gln70Ter variant is pathogenic. This variant has been identified in 0.05257% (142/270128) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965020). 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 a well-known pathogenic variant in Europeans with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (32/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). This variant has also been reported pathogenic in ClinVar (Variation ID: 11909). This nonsense variant leads to a premature termination codon at position 70, 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, and this is a loss of function variant. 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). -
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). -
Mucopolysaccharidosis, MPS-I-S Pathogenic:2
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). -
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:2
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IDUA-related disorder Pathogenic:1
The IDUA c.208C>T variant is predicted to result in premature protein termination (p.Gln70*). This variant has been detected in the homozygous or compound heterozygous state in many individuals with mucopolysaccharidosis Type I (MPSI) and is among the most common causes of disease (Scott et al. 1992. PubMed ID: 1301941; Beesley et al. 2001. PubMed ID: 11735025; Pollard et al. 2013. PubMed ID: 22976768). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-981646-C-T). Nonsense variants in IDUA are expected to be pathogenic. This variant is interpreted as pathogenic. -
Interstitial pneumonitis Pathogenic:1
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Mucopolysaccharidosis Pathogenic:1
This IDUA variant has been reported in several unrelated individuals with mucopolysaccharidosis type 1, either in the homozygous or compound heterozygous state. The variant (rs121965020) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 137/274830 total alleles; 0.05%; no homozygotes), and has been reported in ClinVar (Variation ID 11909). This nonsense variant results in a premature stop codon in exon 2 of 14, likely leading to nonsense-mediated decay and lack of protein production, and this is supported by functional studies. We consider c.208C>T in IDUA to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at