ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.235G>A (p.Ala79Thr) (rs58037052)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000422439 SCV000227056 other not provided 2018-05-25 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000422439 SCV000511059 benign not provided 2017-01-27 criteria provided, single submitter clinical testing
Counsyl RCV000674553 SCV000799908 likely benign Hurler syndrome 2018-05-16 criteria provided, single submitter clinical testing
Invitae RCV000708549 SCV000837659 other Mucopolysaccharidosis type 1 2018-12-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000708549 SCV001317785 benign Mucopolysaccharidosis type 1 2017-04-28 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194419 SCV001363959 benign not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: IDUA c.235G>A (p.Ala79Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 270526 control chromosomes, predominantly at a frequency of 0.031 within the African subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (i.e. 0.031 vs 0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant, c.235G>A, also has been reported in the literature as a well-known pseudodeficiency allele, prevalent in the African American subpopulation. Individuals with pseudodeficiency allele(s) exhibit decreased alpha-L-iduronidase enzyme activity in biochemical assays using artificial substrates, but otherwise show no evidence of disease (see e.g. in Clarke_2016). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as a benign / likely benign pseudodeficiency allele (4x), or VUS (1x). Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000422439 SCV000801292 uncertain significance not provided 2016-07-27 no assertion criteria provided clinical testing

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