rs762903007

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_ModeratePM3PM2_SupportingPP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1139A>G variant in IDUA is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 380 (p.Gln380Arg). This variant has been detected in at least 34 individuals with MPS I. Of those individuals, 20 were compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic variant for MPS I by the ClinGen LD VCEP, all in unknown phase. The second variant includes c.46_57del (p.Ser16_Ala19del) (PMID:35141277) (0.5 pt), c.208C>T (p.Gln70Ter)(11 patients, PMID:24368159, 24875751, 35141277) (max 2 x 0.5 points), c.979G>C p.Ala327Pro (PMID:28752568) (0.5 pt), c.1205G>A p.Trp402Ter (6 patients, PMID:28752568, 35141277) (max 2 x 0.5 pts), c.1861C>T (p.Arg621Ter) ((PMID:11735025) (0.25 pt). Four unrelated individuals are homozygous for the variant PMID:19396826, 31194252, 35141277) (max 2 x 0.5 pts). Total 4.25 points (PM3_VeryStrong). At least 19 patients with this variant had documented IDUA deficiency within the affected range in leukocytes, and/or urinary GAGs expressed as either total GAGs and/or specific GAG elevation above normal range, and/or clinical features specific to MPS I including dysostosis multiplex, corneal clouding, and hepatosplenomegaly (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.10. is 0.00003112 (36/1156956 alleles) in the NFE population (gnomAD v2.1.1 is 0.00004458 with 3/67302 alleles in the NFE 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 0.872 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID:36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 550799). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802202/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 6.01

Publications

10 publications found

Variant links:

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]

IDUA Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 7 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1139A>G	p.Gln380Arg	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.743A>G	p.Gln248Arg	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1139A>G	p.Gln380Arg	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1227A>G		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1139A>G	p.Gln380Arg	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1139A>G	p.Gln380Arg	missense_variant	Exon 8 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1246A>G		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1 link	n.1195A>G		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000182

AC:

AN:

165216

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1412116

Hom.:

Cov.:

AF XY:

0.0000229

AC XY:

AN XY:

698460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31790

American (AMR)

AF:

0.00

AC:

AN:

36646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25326

East Asian (EAS)

AF:

0.00

AC:

AN:

36054

South Asian (SAS)

AF:

0.00

AC:

AN:

80942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

1088964

Other (OTH)

AF:

0.0000512

AC:

AN:

58580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000908

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:2

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000203.5:c.1139A>G variant in IDUA is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 380 (p.Gln380Arg). This variant has been detected in at least 34 individuals with MPS I. Of those individuals, 20 were compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic variant for MPS I by the ClinGen LD VCEP, all in unknown phase. The second variant includes c.46_57del (p.Ser16_Ala19del) (PMID: 35141277) (0.5 pt), c.208C>T (p.Gln70Ter)(11 patients, PMID: 24368159, 24875751, 35141277) (max 2 x 0.5 points), c.979G>C p.Ala327Pro (PMID: 28752568) (0.5 pt), c.1205G>A p.Trp402Ter (6 patients, PMID: 28752568, 35141277) (max 2 x 0.5 pts), c.1861C>T (p.Arg621Ter) ((PMID: 11735025) (0.25 pt). Four unrelated individuals are homozygous for the variant PMID: 19396826, 31194252, 35141277) (max 2 x 0.5 pts). Total 4.25 points (PM3_VeryStrong). At least 19 patients with this variant had documented IDUA deficiency within the affected range in leukocytes, and/or urinary GAGs expressed as either total GAGs and/or specific GAG elevation above normal range, and/or clinical features specific to MPS I including dysostosis multiplex, corneal clouding, and hepatosplenomegaly (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.10. is 0.00003112 (36/1156956 alleles) in the NFE population (gnomAD v2.1.1 is 0.00004458 with 3/67302 alleles in the NFE 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 0.872 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 550799). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PM3_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 380 of the IDUA protein (p.Gln380Arg). This variant is present in population databases (rs762903007, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 11735025, 12559846, 15300847, 17606547, 24368159). ClinVar contains an entry for this variant (Variation ID: 550799). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

IDUA: PM3:Very Strong, PM2, PP3, PP4 -

Hurler syndrome

Pathogenic:2

Oct 09, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 08, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence variant is a single nucleotide substitution (A>G) at position 1139 of the coding sequence of the IDUA gene that results in a glutamine to arginine amino acid change at residue 380 of the alpha-L-iduronidase protein. This is a previously reported variant (ClinVar 550799) that has been observed in homozygous or compound heterozygous state in many individuals and families affected by an attenuated form of mucopolysaccharidosis type I (PMID: 35141277, 19396826, 28752568, 24875751, 31194252, 12203999, 31304092, 12559846, 30120129, 15300847, 17606547, 11735025, 8680403). This variant is present in 39 of 1564204 alleles (0.0025%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Gln380 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant observed a significant decrease in IDUA protein activity in compound heterozygote patient-derived fibroblasts (PMID: 15300847) and plasma (PMID: 24875751), however the clinical significance of these findings is unclear. Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PM3, PP3, PS4 -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome

Pathogenic:1

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;.

PhyloP100

6.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.2

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.051

T;T

Polyphen

0.96

D;.

Vest4

0.73

MVP

0.97

MPC

0.39

ClinPred

0.64

GERP RS

5.3

Varity_R

0.79

gMVP

0.79

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over