ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.296C>T (p.Thr99Ile) (rs147490060)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000400163 SCV000331009 benign not specified 2017-08-25 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000435479 SCV000511610 benign not provided 2017-01-27 criteria provided, single submitter clinical testing
Invitae RCV001082638 SCV001120251 benign Mucopolysaccharidosis type 1 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001082638 SCV001317788 benign Mucopolysaccharidosis type 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000400163 SCV001363958 likely benign not specified 2019-05-02 criteria provided, single submitter clinical testing Variant summary: IDUA c.296C>T (p.Thr99Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 187384 control chromosomes, predominantly at a frequency of 0.023 within the African subpopulation in the gnomAD database (exomes dataset), including 4 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (i.e. 0.023 vs. 0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In the literature, c.296C>T, has been identified during newborn screening for lysosomal storage disorders in an African newborn together with two pseudodeficiency variants that could explain the detected lower enzyme activity (Burlina_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000435479 SCV000801293 benign not provided 2016-07-27 no assertion criteria provided clinical testing

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