ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.208C>T (p.Gln70Ter) (rs121965020)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790700 SCV000227059 pathogenic not provided 2013-08-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000276574 SCV000245622 pathogenic Mucopolysaccharidosis type 1 2014-12-24 criteria provided, single submitter clinical testing 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).
Illumina Clinical Services Laboratory,Illumina RCV000276574 SCV000451736 pathogenic Mucopolysaccharidosis type 1 2017-04-27 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000276574 SCV000695971 pathogenic Mucopolysaccharidosis type 1 2016-08-04 criteria provided, single submitter clinical testing 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.
Invitae RCV000276574 SCV000752528 pathogenic Mucopolysaccharidosis type 1 2019-12-13 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs121965020, ExAC 0.3%). This variant has been reported in the literature as homozygous or in combination with another IDUA variant in several individuals affected with mucopolysaccharidosis type I (PMID: 8401515, 24314423, 21831683, 24368159, 22976768, 21394825). ClinVar contains an entry for this variant (Variation ID: 11909). Experimental studies have shown that this nonsense change diminishes IDUA enzymatic activty (PMID: 21831683). Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763532 SCV000894344 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2018-10-31 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000185562 SCV001164455 pathogenic Mucopolysaccharidosis, MPS-I-H/S 2018-12-03 criteria provided, single submitter research 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).
GeneDx RCV000790700 SCV001168420 pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing The Q70X variant in the IDUA gene is one of the most common pathogenic variants in the IDUA gene, accounting for 19-62% of pathogenic alleles among European or Scandinavian individuals with mucopolysaccharidosis type I (MPS I) when present in the homozygous state or in trans with another pathogenic variant (Bunge et al., 1994; Pollard et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies showed very low IDUA activity (0.1-0.2% of controls) in fibroblast cell lines from individuals homozygous for this variant (Oussoren et al., 2013 ). Consistent with the high prevalence of this variant among affected individuals of European descent, the Q70X variant is observed in 53/25,426 alleles (0.21%) from individuals of Finnish background, and 142/270,128 global alleles (0.05%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). We interpret Q70X as a pathogenic variant.
Myriad Women's Health, Inc. RCV000012684 SCV001194218 pathogenic Hurler syndrome 2019-11-12 criteria provided, single submitter clinical testing 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.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000276574 SCV001251495 pathogenic Mucopolysaccharidosis type 1 criteria provided, single submitter research 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).
OMIM RCV000012684 SCV000032919 pathogenic Hurler syndrome 2001-11-01 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000012684 SCV000238450 pathogenic Hurler syndrome 2015-03-04 no assertion criteria provided research 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).
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185562 SCV000238451 pathogenic Mucopolysaccharidosis, MPS-I-H/S 2015-03-04 no assertion criteria provided research 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).
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185563 SCV000238452 pathogenic Mucopolysaccharidosis, MPS-I-S 2015-03-04 no assertion criteria provided research 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).
GeneReviews RCV000276574 SCV000264376 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group,Broad Institute RCV000276574 SCV001422679 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation 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).

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