ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.979G>C (p.Ala327Pro) (rs199801029)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790804 SCV000232484 pathogenic not provided 2014-01-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208605 SCV000695977 pathogenic Mucopolysaccharidosis type 1 2017-08-02 criteria provided, single submitter clinical testing Variant summary: The IDUA c.979G>C (p.Ala327Pro) variant involves the alteration of a non-conserved nucleotide located in the Glycoside hydrolase superfamily domain (IPR017853) (InterPro). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively). Functional studies found very low enzymatic residual activity in homozygote and compound heterozygote MPS I patients (Oussorena__2013, Yogalingam_2004). The variant of interest has been found in a large, broad control population, ExAC in 7/90286 control chromosomes at a frequency of 0.0000775, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). This variant was found in multiple patients with MPS I, including homozygotes and compound heterozygotes (in trans with pathogenic variants such as c.878-889dup12, c.1205G>A/p.W402X, c.1154C>G/p.P385R, and c.1148G>A/R383H), and determined to be associated with a severe phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000180108 SCV000791720 pathogenic Hurler syndrome 2017-05-22 criteria provided, single submitter clinical testing
Invitae RCV000208605 SCV000834627 pathogenic Mucopolysaccharidosis type 1 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 327 of the IDUA protein (p.Ala327Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs199801029, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with mucopolysaccharidosis type I (PMID: 19396826). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported as homozygous and in combination with another IDUA variant in individuals affected with mucopolysaccharidosis type I (PMID: 7550242, 23786846, 24368159, 15300847). This variant is also known as c.1067G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 167190). Studies in patient cells have shown that this missense change results in a reduction of the IDUA enzymatic activity (PMID: 23786846, 15300847). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000208605 SCV000929873 likely pathogenic Mucopolysaccharidosis type 1 2019-01-01 criteria provided, single submitter literature only PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in GnomAD
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000208605 SCV001251528 pathogenic Mucopolysaccharidosis type 1 criteria provided, single submitter research The IDUA c.979G>C (p.A327P) variant was reported in the compound heterozygous state in at least 4 patients with MPS I (PMID: 7550242; 112203999; 15300847; 19396826; 24368159).
Johns Hopkins Genomics, Johns Hopkins University RCV000180108 SCV001425318 pathogenic Hurler syndrome 2020-04-29 criteria provided, single submitter clinical testing This IDUA variant has been previously reported in patients with mucopolysaccharidosis I in the presence of a second known disease-causing variant. Although the alanine residue at this position is not evolutionarily conserved across species assessed, funcational analysis in patient cells support that c.979G>C results in reduced IDUA ensymatic activity. This variant (rs199801029) is rare (<0.1%) in a large population dataset (gnomAD: 19/273938 total alleles; 0.006936%; no homozygotes). Six submitters in ClinVar6 classify this variant as either pathogenic or likely pathogenic. We consider it to be pathogenic.
GeneDx RCV000790804 SCV001796972 pathogenic not provided 2020-02-07 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 30809705, 27896125, 8680403, 21394825, 27392569, 27511503, 28684085, 28752568, 10607946, 23786846, 9427149, 7550242, 24368159, 7951228, 15300847)
GeneReviews RCV000208605 SCV000264382 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208605 SCV001422985 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Ala327Pro variant in IDUA has been reported in at least 23 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 23786846, 7550242, 19396826, 24368159) and has been identified in 0.012% (15/123926) of European (non-Finnish) chromosomes, 0.006% (2/34992) of Latino chromosomes, and 0.004% (1/24138) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199801029). 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 has also been reported in ClinVar (VariationID: 167190) as pathogenic by Counsyl, EGL Genetic Diagnostics, Integrated Genetics, Invitae, and GeneReviews. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on their Alpha-L-iduronidase levels being <1% of normal consistent with disease (PMID: 23786846). The presence of this variant in 3 affected homozygotes and in combination with a reported pathogenic variant in at least 14 individuals with MPS increases the likelihood that the p.Ala327Pro variant is pathogenic (VariationID: 11908; PMID: 28752568, 23786846, 7550242, 19396826). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences in combination with other pathogenic variants in individuals with MPS and the phenotype of patients with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP4 (Richards 2015).
Natera, Inc. RCV000208605 SCV001461759 pathogenic Mucopolysaccharidosis type 1 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000790804 SCV001740921 pathogenic not provided no assertion criteria provided clinical testing

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