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

gnomAD frequency: 0.01974  dbSNP: rs11934801

Total submissions: 13

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
Labcorp Genetics (formerly Invitae), Labcorp	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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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