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: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1091C>T	p.Thr364Met	missense	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.695C>T	p.Thr232Met	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1179C>T		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1091C>T	p.Thr364Met	missense	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1091C>T	p.Thr364Met	missense	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1166C>T	p.Thr389Met	missense	Exon 9 of 15	ENSP00000632448.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
1	-	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	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;