rs121965020
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000203.5(IDUA):c.208C>T(p.Gln70Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000491 in 1,612,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00048 ( 0 hom. )
Consequence
IDUA
NM_000203.5 stop_gained
NM_000203.5 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 3.66
Genes affected
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-987858-C-T is Pathogenic according to our data. Variant chr4-987858-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987858-C-T is described in Lovd as [Pathogenic]. Variant chr4-987858-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| IDUA | NM_000203.5 | c.208C>T | p.Gln70Ter | stop_gained | 2/14 | ENST00000514224.2 | |
| SLC26A1 | NM_022042.4 | c.*975G>A | 3_prime_UTR_variant | 3/3 | ENST00000398516.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| IDUA | ENST00000514224.2 | c.208C>T | p.Gln70Ter | stop_gained | 2/14 | 2 | NM_000203.5 | P1 | |
| SLC26A1 | ENST00000398516.3 | c.*975G>A | 3_prime_UTR_variant | 3/3 | 1 | NM_022042.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000578 AC: 88AN: 152192Hom.: 0 Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 09, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | IDUA: PM3:Very Strong, PVS1, PM2 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2020 | 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 13, 2023 | - - |
Mucopolysaccharidosis type 1 Pathogenic:7Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | Common variant in Europe and Russia; associated with severe MPS I - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2016 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 24, 2014 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 13, 2020 | 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). - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | 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). - |
Hurler syndrome Pathogenic:4
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 04, 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Oct 24, 2019 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | 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. - |
Mucopolysaccharidosis, MPS-I-H/S Pathogenic:2
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 04, 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). - |
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | 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). - |
Mucopolysaccharidosis, MPS-I-S Pathogenic:2
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Mar 04, 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 12, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
IDUA-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 29, 2022 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Mucopolysaccharidosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Aug 06, 2023 | 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. - |
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 08, 2022 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A;A
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at