rs199801029

chr4-1002275-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000203.5(IDUA):c.979G>C(p.Ala327Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A327A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 0.419

Genes affected

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 4-1002275-G-C is Pathogenic according to our data. Variant chr4-1002275-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1002275-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.979G>C	p.Ala327Pro	missense_variant	8/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.979G>C	p.Ala327Pro	missense_variant	8/14	2	NM_000203.5	P1
IDUA	ENST00000247933.9	c.979G>C	p.Ala327Pro	missense_variant	8/14	1		P1
IDUA	ENST00000514698.5	n.1086G>C		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1035G>C		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000660 AC: 16 AN: 242572 Hom.: 0 AF XY: 0.0000606 AC XY: 8 AN XY: 131990

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1458728 Hom.: 0 Cov.: 35 AF XY: 0.000128 AC XY: 93 AN XY: 725556

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2017	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	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). -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant in Europe -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2019	PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in GnomAD -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	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. -

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	IDUA: PM3:Very Strong, PM2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	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) -

Hurler syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 29, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 22, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.90	D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.69
Sift	Benign	0.22	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.34	B;.
Vest4		0.84
MVP		0.98
MPC		0.32
ClinPred		0.18	T
GERP RS		3.6
Varity_R		0.67
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199801029; hg19: chr4-996063;