Submissions for variant NM_000203.5(IDUA):c.979G>C (p.Ala327Pro)

gnomAD frequency: 0.00008  dbSNP: rs199801029

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790804	SCV000232484	pathogenic	not provided	2014-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000208605	SCV000695977	pathogenic	Mucopolysaccharidosis type 1	2017-08-02	criteria provided, single submitter	clinical testing	Variant summary: The IDUA c.979G>C (p.Ala327Pro) variant involves the alteration of a non-conserved nucleotide located in the Glycoside hydrolase superfamily domain (IPR017853) (InterPro). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively). Functional studies found very low enzymatic residual activity in homozygote and compound heterozygote MPS I patients (Oussorena__2013, Yogalingam_2004). The variant of interest has been found in a large, broad control population, ExAC in 7/90286 control chromosomes at a frequency of 0.0000775, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). This variant was found in multiple patients with MPS I, including homozygotes and compound heterozygotes (in trans with pathogenic variants such as c.878-889dup12, c.1205G>A/p.W402X, c.1154C>G/p.P385R, and c.1148G>A/R383H), and determined to be associated with a severe phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl	RCV000180108	SCV000791720	pathogenic	Hurler syndrome	2017-05-22	criteria provided, single submitter	clinical testing
Invitae	RCV000208605	SCV000834627	pathogenic	Mucopolysaccharidosis type 1	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 327 of the IDUA protein (p.Ala327Pro). This variant is present in population databases (rs199801029, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 7550242, 15300847, 19396826, 23786846, 24368159). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1067G>C. ClinVar contains an entry for this variant (Variation ID: 167190). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 15300847, 23786846). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000208605	SCV000929873	likely pathogenic	Mucopolysaccharidosis type 1	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in GnomAD
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000208605	SCV001251528	pathogenic	Mucopolysaccharidosis type 1		criteria provided, single submitter	research	The IDUA c.979G>C (p.A327P) variant was reported in the compound heterozygous state in at least 4 patients with MPS I (PMID: 7550242; 112203999; 15300847; 19396826; 24368159).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208605	SCV001422985	pathogenic	Mucopolysaccharidosis type 1	2020-01-13	criteria provided, single submitter	curation	The p.Ala327Pro variant in IDUA has been reported in at least 23 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 23786846, 7550242, 19396826, 24368159) and has been identified in 0.012% (15/123926) of European (non-Finnish) chromosomes, 0.006% (2/34992) of Latino chromosomes, and 0.004% (1/24138) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199801029). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 167190) as pathogenic by Counsyl, EGL Genetic Diagnostics, Integrated Genetics, Invitae, and GeneReviews. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on their Alpha-L-iduronidase levels being <1% of normal consistent with disease (PMID: 23786846). The presence of this variant in 3 affected homozygotes and in combination with a reported pathogenic variant in at least 14 individuals with MPS increases the likelihood that the p.Ala327Pro variant is pathogenic (VariationID: 11908; PMID: 28752568, 23786846, 7550242, 19396826). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences in combination with other pathogenic variants in individuals with MPS and the phenotype of patients with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP4 (Richards 2015).
Johns Hopkins Genomics, Johns Hopkins University	RCV000180108	SCV001425318	pathogenic	Hurler syndrome	2020-04-29	criteria provided, single submitter	clinical testing	This IDUA variant has been previously reported in patients with mucopolysaccharidosis I in the presence of a second known disease-causing variant. Although the alanine residue at this position is not evolutionarily conserved across species assessed, funcational analysis in patient cells support that c.979G>C results in reduced IDUA ensymatic activity. This variant (rs199801029) is rare (<0.1%) in a large population dataset (gnomAD: 19/273938 total alleles; 0.006936%; no homozygotes). Six submitters in ClinVar6 classify this variant as either pathogenic or likely pathogenic. We consider it to be pathogenic.
GeneDx	RCV000790804	SCV001796972	pathogenic	not provided	2020-02-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 30809705, 27896125, 8680403, 21394825, 27392569, 27511503, 28684085, 28752568, 10607946, 23786846, 9427149, 7550242, 24368159, 7951228, 15300847)
Revvity Omics, Revvity	RCV000790804	SCV002023111	pathogenic	not provided	2023-06-06	criteria provided, single submitter	clinical testing
GeneReviews	RCV000208605	SCV000264382	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Common pathogenic variant in Europe
Natera, Inc.	RCV000208605	SCV001461759	pathogenic	Mucopolysaccharidosis type 1	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000790804	SCV001740921	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000790804	SCV001975512	pathogenic	not provided		no assertion criteria provided	clinical testing