4-1002387-C-T

Variant names:

• chr4-1002387-C-T
• rs121965032
• NM_000203.5:c.1091C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP4_Moderate PM2_Supporting PM3_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1091C>T variant in IDUA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 364 (p.Thr364Met). This variant has been identified in at least 6 probands with MPS I. Three individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.613_617dup (p.Glu207fs) (ClinVar Variation ID: 11921); phase unconfirmed (PMID:15521993) (max 2 x 0.5 points = 1 point). Two individuals were apparently homozygous for the variant (PMID:9391892, 16435211; 2 x 0.5 points; one of them is possibly compound heterozygous for the variant and a gene deletion) (PMID:9391892). Another individual is compound heterozygous for the variant and c.589G>A p.(Gly197Ser) (PMID:33301762). The allelic data from this patient will be used in the assessment of p.Gly197Ser and is not included here to avoid circular logic. Total 2 points (PM3_Strong). Patients reported with this variant had features specific to MPS I, including one patient with clinical symptoms consistent with the diagnosis, documented IDUA deficiency, and elevated urine GAGs that reduced upon treatment with ERT (PMID:16435211) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002245 (1/44544 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in COS-7 cells resulted in ~1% wild type IDUA activity and evidence of abnormal IDUA synthesis and processing indicating that this variant may impact protein function (PMIDs: 9391892, 10466419; PS3_Supporting). The computational predictor REVEL gives a score of 0.908 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: : 11925). In summary, this variant meets the criteria to be classified as 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_Moderate,, PM2_Supporting, PS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, May 16, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256126/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 4.79
• Publications: 12 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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	c.1091C>T	p.Thr364Met	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.695C>T	p.Thr232Met	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1091C>T	p.Thr364Met	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1179C>T		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1091C>T	p.Thr364Met	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1091C>T	p.Thr364Met	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1198C>T		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1147C>T		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455338 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 723550

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.00 AC: 0 AN: 43998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39362

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109472

Other (OTH) AF: 0.00 AC: 0 AN: 60126

GnomAD4 genome Cov.: 34

Alfa AF: 0.000533 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 364 of the IDUA protein (p.Thr364Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 9391892, 16435211, 29801497). ClinVar contains an entry for this variant (Variation ID: 11925). 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: 9391892, 10466419). This variant disrupts the p.Thr364 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

May 16, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.1091C>T variant in IDUA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 364 (p.Thr364Met). This variant has been identified in at least 6 probands with MPS I. Three individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.613_617dup (p.Glu207fs) (ClinVar Variation ID: 11921); phase unconfirmed (PMID: 15521993) (max 2 x 0.5 points = 1 point). Two individuals were apparently homozygous for the variant (PMID: 9391892, 16435211; 2 x 0.5 points; one of them is possibly compound heterozygous for the variant and a gene deletion) (PMID: 9391892). Another individual is compound heterozygous for the variant and c.589G>A p.(Gly197Ser) (PMID: 33301762). The allelic data from this patient will be used in the assessment of p.Gly197Ser and is not included here to avoid circular logic. Total 2 points (PM3_Strong). Patients reported with this variant had features specific to MPS I, including one patient with clinical symptoms consistent with the diagnosis, documented IDUA deficiency, and elevated urine GAGs that reduced upon treatment with ERT (PMID: 16435211) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002245 (1/44544 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in COS-7 cells resulted in ~1% wild type IDUA activity and evidence of abnormal IDUA synthesis and processing indicating that this variant may impact protein function (PMIDs: 9391892, 10466419; PS3_Supporting). The computational predictor REVEL gives a score of 0.908 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: : 11925). In summary, this variant meets the criteria to be classified as 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_Moderate,, PM2_Supporting, PS3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, May 16, 2025). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.1091C>T (p.Thr364Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234716 control chromosomes (gnomAD). c.1091C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Lee-Chen_1997, Sun_2011, Chuang_2018, Thomas_2021). These data indicate that the variant is likely to be associated with disease. Functional studies showed that the variant of interest leads to decreased level of mRNA and extremely low levels of protein and enzyme activity (e.g. Lee-Chen_1997, Lee-Chen_1999). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1

Nov 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 05, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome Pathogenic:1

Jul 12, 2019

Counsyl

Significance: Likely 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. -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.87
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.81
gMVP		0.85
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121965032; hg19: chr4-996175;