NM_000203.5:c.1598C>G

Variant names:

• chr4-1003418-C-G
• rs121965021
• NM_000203.5:c.1598C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP1_Moderate PP4_Moderate PM2_Supporting PM3 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1598C>G variant in IDUA is a missense variant that is predicted to result in the substitution of proline by arginine at amino acid 533 (p.Pro533Arg). This variant is one of the more common variants identified in patients with mucopolysaccharidosis type 1 (MPS 1). The variant was found in 46 out of 538 patients in the International MPS 1 Registry (PMID:31194252). It has been identified in patients with MPS 1 from different continents, and it is the most frequent variant in the north African countries (92% of MPS1 alleles in Morocco, 81% in Algeria, and 54% in Tunisia) (reviewed in PMID:29393969). Of note, the severity of symptoms in individuals with this variant is variable; some homozygous individuals have severe disease while others have attenuated symptoms (PMID:31194252). At least 50 patients with this variant have been reported including patients with documented laboratory values showing deficient iduronidase activity and detailed features consistent with MPS 1 such as dysmorphic facies, multiple dysostoses, joint stiffness, hepatomegaly, umbilical hernia, hearing loss, cardiovascular disease, and hydrocephalus and/or elevated urine GAGs (2 PP4 criteria met) (PMID:10738517, 12796790, 1301941). One study provides details on the clinical features, IDUA activity, and GAG values for 9 patients (3 PP4 criteria met, PMID:27196898) (PP4_Moderate). At least 24 individuals are homozygous for the variant (PMID:1301941, 10738517, 12203999, 16435195, 24102521, 27196898, 28752568, 31194252, 31298590). At least 12 individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, including at least 8 patients with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (max 2 x 0.5 points), two patients with c.208C>T (p.Gln70Ter) (PMID:31194252) (ClinVar Variation ID: 11909) (2 x 0.5 points), two apparently unrelated patients with c.1743C>G (p.Tyr581Ter) (ClinVar Variation ID: 550883) (2 x 0.5 points), and at least 24 homozygotes (max 2 x 0.5 points) (PMID:31194252). 4 PM3 points (PM3_VeryStrong). Many additional individuals have been reported who are compound heterozygous for additional IDUA variants (PMID:12203999, 12559846, 31194252). Additional evidence is available in the literature but the maximum points for PM3 have been reached (PM3_Very Strong). The variant has been shown to segregate with disease in families, including two families each with two affected children who are homozygous for the variant (PMID:27196898) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001975 (10/50624 alleles) in the Admixed American 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 CHO cells and tobacco BY-2 cells revealed that the protein is unstable, abnormally processed/trafficked, and has very low, but detectable (<1%), residual activity when compared to wild type (PMID:12559846, 24036510) (PS3_Supporting). The computational predictor REVEL gives a score of 0.783 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). No impact on splicing predicted by SpliceAI. There is a ClinVar entry for this variant (Variant ID: 11910). In summary, this variant meets the criteria to be classified as pathogenic for MPS 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256112/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 2.91
• Publications: 76 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.
• PP1: 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.1598C>G	p.Pro533Arg	missense	Exon 11 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1202C>G	p.Pro401Arg	missense	Exon 10 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1686C>G		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1598C>G	p.Pro533Arg	missense	Exon 11 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1598C>G	p.Pro533Arg	missense	Exon 11 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1673C>G	p.Pro558Arg	missense	Exon 12 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000555 AC: 7 AN: 126026 AF XY: 0.0000289

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000636

Gnomad OTH exome AF: 0.000258

GnomAD4 exome AF: 0.0000298 AC: 41 AN: 1376970 Hom.: 0 Cov.: 33 AF XY: 0.0000353 AC XY: 24 AN XY: 679424

African (AFR) AF: 0.00 AC: 0 AN: 30626

American (AMR) AF: 0.000226 AC: 8 AN: 35348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24912

East Asian (EAS) AF: 0.00 AC: 0 AN: 35058

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 0.0000232 AC: 25 AN: 1076680

Other (OTH) AF: 0.000104 AC: 6 AN: 57462

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000217 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Mucopolysaccharidosis type 1 (6)
5	-	-	not provided (5)
3	-	-	Hurler syndrome (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.99
MPC		0.78
ClinPred		0.82	D
GERP RS		4.3
Varity_R		0.91
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121965021; hg19: chr4-997206;