Submissions for variant NM_000203.5(IDUA):c.1349C>A (p.Pro450His)

gnomAD frequency: 0.00002  dbSNP: rs895626490

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781474	SCV000919532	uncertain significance	not specified	2017-12-07	criteria provided, single submitter	clinical testing	Variant summary: The IDUA c.1349C>A (p.Pro450His) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 3/30770 control chromosomes at a frequency of 0.0000975, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Illumina Laboratory Services, Illumina	RCV001152716	SCV001313943	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001152716	SCV001415064	uncertain significance	Mucopolysaccharidosis type 1	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 450 of the IDUA protein (p.Pro450His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 633271). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270128	SCV001448997	uncertain significance	Hurler syndrome	2019-11-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001152716	SCV003835994	uncertain significance	Mucopolysaccharidosis type 1	2022-11-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001152716	SCV001457285	uncertain significance	Mucopolysaccharidosis type 1	2020-01-24	no assertion criteria provided	clinical testing