ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1225G>C (p.Gly409Arg)

gnomAD frequency: 0.01974  dbSNP: rs11934801
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000078375 SCV000110221 benign not specified 2015-03-09 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000078375 SCV000257642 uncertain significance not specified 2015-06-08 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000327434 SCV000451786 likely benign Mucopolysaccharidosis type 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000418377 SCV000510695 benign not provided 2016-09-08 criteria provided, single submitter clinical testing
Invitae RCV000327434 SCV000752535 benign Mucopolysaccharidosis type 1 2024-02-01 criteria provided, single submitter clinical testing
Mendelics RCV000722002 SCV001136677 likely benign Hurler syndrome 2019-05-28 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000327434 SCV001422670 benign Mucopolysaccharidosis type 1 2020-01-13 criteria provided, single submitter curation The p.Gly409Arg variant has not been previously reported in individuals with mucopolysaccharidosis (MPS) but has been identified in 5.567% (555/9810) of African chromosomes, including 16 homozygotes, and 3 additional homozygotes in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs11934801). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as benign by Invitae, EGL Genetic Diagnostics, and Children's Mercy Hospital and Clinics, likely benign by Illumina, and a VUS by the Children's Hospital of Philadelphia and the NUS Institute of Precision Medicine (Variation ID: 92627). It has also been reported in the heterozygous state and described as a pseudodeficiency allele in an unaffected individual from newborn screening, suggesting that this variant is not pathogenic for disease (PMID: 31133280). In summary, this variant meets criteria to be classified as benign for mucopolysaccharidosis in an autosomal recessive manner based on the high frequency of the variant in the general population. ACMG/AMP Criteria applied: BA1, BS2 (Richards 2015).
GeneDx RCV000418377 SCV001782052 likely benign not provided 2020-12-04 criteria provided, single submitter clinical testing Appears to be a hypomorphic allele. Functional studies indicate that this variant reduces protein activity to 61% (Bach et al., 1993), which is not in the pathogenic range for this enzyme.; This variant is associated with the following publications: (PMID: 30709774, 31133280, 28676128, 27335677, 8328452, 21228398)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078375 SCV002500155 benign not specified 2022-03-07 criteria provided, single submitter clinical testing Variant summary: IDUA c.1225G>C (p.Gly409Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 118354 control chromosomes (gnomAD), predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign.
SingHealth Duke-NUS Institute of Precision Medicine RCV000722002 SCV000853166 uncertain significance Hurler syndrome 2017-06-07 no assertion criteria provided curation
Clinical Genetics, Academic Medical Center RCV000418377 SCV001925453 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000078375 SCV001928974 benign not specified no assertion criteria provided clinical testing
Natera, Inc. RCV000327434 SCV002075347 benign Mucopolysaccharidosis type 1 2020-04-23 no assertion criteria provided clinical testing

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