ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1855C>T (p.Arg619Ter)

gnomAD frequency: 0.00004  dbSNP: rs121965031
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723407 SCV000330968 pathogenic not provided 2016-03-22 criteria provided, single submitter clinical testing
Counsyl RCV000337972 SCV000791239 pathogenic Hurler syndrome 2017-05-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780351 SCV000917541 pathogenic Mucopolysaccharidosis type 1 2018-07-02 criteria provided, single submitter clinical testing Variant summary: IDUA c.1855C>T (p.Arg619X) 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 2.5e-05 in 119432 control chromosomes (ExAC). The variant, c.1855C>T, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 with limited to no IDUA enzyme activity detected (Beesley_2001, Uttarilli_2016). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000780351 SCV001422982 pathogenic Mucopolysaccharidosis type 1 2020-01-13 criteria provided, single submitter curation The p.Arg619Ter variant in IDUA has been reported in at least 12 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 11735025, 27146977) and has been identified in 0.001% (1/112290) of European (non-Finnish) chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965031). 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: 280976) as pathogenic by EGL Genetic Diagnostics and Counsyl. This nonsense variant leads to a premature termination codon at position 619. This alteration occurs in the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The phenotype of individuals homozygous for this variant is highly specific for MPS based on very low alpha-L-iduronidase activity consistent with disease (PMID: 27146977). The presence of this variant in 6 affected homozygotes and in combination with reported pathogenic variants in at least 5 individuals with MPS increases the likelihood that the p.Arg619Ter variant is pathogenic (VariationID: 11908, 11909, 11910, 496834; PMID: 28752568, 11735025, 27146977). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it results in a truncated protein, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2, PP4 (Richards 2015).
Invitae RCV000780351 SCV001588715 pathogenic Mucopolysaccharidosis type 1 2023-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg619*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the IDUA protein. This variant is present in population databases (rs121965031, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (MPS I) (PMID: 11735025, 27146977, 28752568). ClinVar contains an entry for this variant (Variation ID: 280976). For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV000780351 SCV002075390 pathogenic Mucopolysaccharidosis type 1 2020-07-22 no assertion criteria provided clinical testing

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