Submissions for variant NM_000203.5(IDUA):c.1893del (p.Phe632fs)

dbSNP: rs1553917754

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587377	SCV000695970	likely pathogenic	Mucopolysaccharidosis type 1	2020-10-09	criteria provided, single submitter	clinical testing	Variant summary: IDUA c.1893delC (p.Phe632SerfsX77+) causes a frameshift which results in an extension of the protein. The variant was absent in 248970 control chromosomes (gnomAD). c.1893delC has been reported in the literature in individuals (compound heterozygous and homozygous) affected with Hurler syndrome - a severe form of Mucopolysaccharidosis Type 1 (Bertola_2011, Oussoren_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000587377	SCV001423020	likely pathogenic	Mucopolysaccharidosis type 1	2020-01-22	criteria provided, single submitter	curation	The p.Phe632Serfs variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 29906569) and was absent from large population studies. This variant has been reported in ClinVar (VariationID: 495733) as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 632. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in an affected homozygote increases the likelihood that the p.Phe632Serfs variant is pathogenic (PMID: 29906569). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2, PM3_supporting (Richards 2015).
Invitae	RCV000587377	SCV004292286	pathogenic	Mucopolysaccharidosis type 1	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the IDUA gene (p.Phe632Serfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the IDUA protein and extend the protein by an uncertain number of additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with Hurler syndrome (PMID: 21394825). ClinVar contains an entry for this variant (Variation ID: 495733). This variant disrupts a region of the IDUA protein in which other variant(s) (p.Ser633Leu) have been determined to be pathogenic (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000984187	SCV001132230	likely pathogenic	Hurler syndrome	2017-07-25	no assertion criteria provided	clinical testing