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

gnomAD frequency: 0.00910  dbSNP: rs58037052

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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 Laboratory Services, 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	2021-11-01	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 or African-American subpopulation in the gnomAD database, including 9 homozygotes. The observed variant frequency within African or African-American 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 (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). Seven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign pseudodeficiency allele (n=6) or VUS (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000422439	SCV001784074	benign	not provided	2018-09-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27939258)
Fulgent Genetics, Fulgent Genetics	RCV002500480	SCV002811181	likely benign	Nephrolithiasis, calcium oxalate	2021-07-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000422439	SCV000801292	uncertain significance	not provided	2016-07-27	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000422439	SCV001800421	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001194419	SCV001921769	benign	not specified		no assertion criteria provided	clinical testing
GeneReviews	RCV000708549	SCV002016347	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Pseudodeficiency variants