Submissions for variant NM_000203.5(IDUA):c.787A>T (p.Arg263Trp)

gnomAD frequency: 0.00009  dbSNP: rs201268637

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665392	SCV000789508	uncertain significance	Hurler syndrome	2017-02-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153898	SCV001315208	uncertain significance	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001153898	SCV001417589	uncertain significance	Mucopolysaccharidosis type 1	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 263 of the IDUA protein (p.Arg263Trp). This variant is present in population databases (rs201268637, gnomAD 0.05%). This missense change has been observed in individual(s) with a positive newborn screening result for IDUA-related disease (PMID: 29143201, 30442156). ClinVar contains an entry for this variant (Variation ID: 550605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282298	SCV002570532	uncertain significance	not specified	2022-07-19	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.787A>T (p.Arg263Trp) 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 0.00013 in 193392 control chromosomes. This frequency is not higher than expected for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00013 vs 0.0027), allowing no conclusion about variant significance. c.787A>T has been reported in the literature in individuals with a positive newborn screening result for IDUA-related disease or diagnosed with pseudo mucopolysaccharidosis in homozygous or compound heterozygous state (examples: Burlina_2018, Donati_2018, Taylor_2019 and Polo_2020). These reports do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000675604	SCV003809998	uncertain significance	not provided	2023-10-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000675604	SCV000801301	uncertain significance	not provided	2017-06-07	no assertion criteria provided	clinical testing
GeneReviews	RCV001153898	SCV002016349	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Pseudodeficiency variants
Natera, Inc.	RCV001153898	SCV002075313	uncertain significance	Mucopolysaccharidosis type 1	2020-06-01	no assertion criteria provided	clinical testing