Submissions for variant NM_000203.5(IDUA):c.806C>G (p.Ser269Cys)

gnomAD frequency: 0.00025  dbSNP: rs202051939

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001154740	SCV001316120	uncertain significance	Mucopolysaccharidosis type 1	2018-01-12	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	RCV001154740	SCV001413630	uncertain significance	Mucopolysaccharidosis type 1	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 269 of the IDUA protein (p.Ser269Cys). This variant is present in population databases (rs202051939, gnomAD 0.07%). 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: 905910). 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. 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	RCV001375619	SCV001572540	uncertain significance	not specified	2021-04-15	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.806C>G (p.Ser269Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 203588 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00037 vs 0.0027), allowing no conclusion about variant significance. c.806C>G has been reported in the literature in compound heterozygosity with IDUA c.757G>T (p.Gly253Cys) in a prenatal case of Nonimmune hydrops fetalis. A homozygous occurrence of SUMF1 c.691dupT (p.Trp231LeufsX11) was also detected in this case which was diagnostic for multiple sulfatase deficiency (Al-Kouatly_2021). This report does not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001760110	SCV001999404	uncertain significance	not provided	2019-10-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28676128)
Revvity Omics, Revvity	RCV001760110	SCV003817631	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001154740	SCV002075317	uncertain significance	Mucopolysaccharidosis type 1	2020-04-15	no assertion criteria provided	clinical testing