Submissions for variant NM_000203.5(IDUA):c.793G>C (p.Gly265Arg)

gnomAD frequency: 0.00003  dbSNP: rs369090960

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000790540	SCV005619875	likely pathogenic	Mucopolysaccharidosis type 1	2024-12-06	reviewed by expert panel	curation	The NM_000203.5:c.793G>C variant in IDUA is a missense variant predicted to cause substitution of glycine by arginine at amino acid 265 (p.Gly265Arg). The variant alters the first nucleotide of exon 7. RNA from two patients with this variant, has been analyzed and includes normally spliced transcripts with the p.Gly265Arg substitution (PMID: 15300847). In one of these patients, transcripts with a 33 bp deletion resulting from use of a cryptic splice site (c.793_825del; p.G265_Q275del) were also detected (PMID: 15300847). Because the impact of this variant on splicing appears to vary, PVS1 will not be applied here at any strength. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, 10 were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic (variants: c.46_57del, c.1205G>A, c.1487C>G, c.208C>T, and c.979G>C) and none of those were confirmed in trans (PMIDs: 31194252, 30809705, 21394825, 11172140, 35787971) (PM3_Strong). At least 2 patients with this variant had documented deficient IDUA activity in leukocytes, but specific values were not provided, and clinical features consistent with MPS I, including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PMID: 11172140) (PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001341 (1/74596 alleles) in the African / African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.93 which is above the threshold of 0.773, evidence that correlates with a damaging impact to IDUA function at the moderate level (PP3_Moderate) In addition, SpliceAI give a score of 0.39 for acceptor loss, suggesting that this variant may impact splicing. There is a ClinVar entry for this variant (Variation ID: 638074). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PM3_Strong, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000790540	SCV000929872	likely pathogenic	Mucopolysaccharidosis type 1	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vivo enzymatic activity in homozygote; low in vitro enzymatic activity. PM2: Very low frequency in ExAC. PP3: Multiple lines of computational evidence evidence supporting a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV000790540	SCV001590399	pathogenic	Mucopolysaccharidosis type 1	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 265 of the IDUA protein (p.Gly265Arg). It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369090960, gnomAD 0.001%). This missense change has been observed in individual(s) with Scheie or Hurler-Scheie syndrome, the attenuated forms of mucopolysaccharidosis type I (PMID: 15300847, 21394825, 31194252). ClinVar contains an entry for this variant (Variation ID: 638074). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects IDUA function (PMID: 15300847). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001784404	SCV002016685	likely pathogenic	not provided	2021-09-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000790540	SCV002075316	pathogenic	Mucopolysaccharidosis type 1	2021-09-29	no assertion criteria provided	clinical testing