rs781136336

Variant names:

• chr4-1003397-T-C
• rs781136336
• NM_000203.5:c.1577T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-1003397-T-C
• chr4-1003397-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM3 PP4 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1577T>C variant in IDUA is a missense variant predicted to cause substitution of leucine by proline at amino acid 526 (p.Leu526Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0005078 (42/82710 alleles) in the South Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), and lower than the threshold for BS1 (>0.0025). Therefore, none of the population data codes are met. At least 12 individuals have been reported with biallelic variants in IDUA (not including pseudodeficiency variants). Eight of those individuals were identified by a newborn screen, all with low IDUA activity, but all with normal total GAGs, and either normal or mildly elevated dermatan and heparan sulfate; two of these individuals were described as having an attenuated phenotype based on clinical evaluation, and others as suspected or undetermined diagnosis (30442156, 30093709, 32432561, 33072983, 33147872, 35787971, 37516270, Greenwood Genetic Center). At least 3 other individuals have been reported to have symptoms consistent with MPS I (22976768, 26260077, 31194252, 37181073). One individual with the variant has been reported with an extremely attenuated phenotype (PMID:37181073). This individual, who is compound heterozygous for the variant and c.228T>A (p.Tyr76Ter), confirmed in trans by parental testing (1 point for PM3), was diagnosed with MPS I at age 38 years. She presented with valvular disease, retinopathy, short stature, dysostosis multiplex, and coarse facial features, and had deficient IDUA activity and elevated urine and serum dermatan and heparan sulfate (elevations were mild) (PP4 met based on clinical symptoms and IDUA deficiency). Another patient, reported to be on ERT and to have skeletal features of MPS I (PMID:26260077, 31194252; may be the same patient in both papers) is compound heterozygous for the variant and c.1205G>A (p.Trp402Ter) (PMID:26260077, 3119425) in unknown phase (0.5 points for PM3). Data from another patient, compound heterozygous for the variant and p.Gln70Ter, were not included due to lack of GAG levels, and the presence of a pseudodeficiency variant (PMID:22976768; personal communication). Total 1.5 points (PM3) However, 27-year-old female, who is compound heterozygous for p.Leu526Pro and c.1205G>A (p.Tyr402Ter), confirmed in trans, has no clinical features of MPS I based on detailed physical exam. Although she has elevated NRE marker UA-HNAc(1S), the elevation is not of the degree observed in affected individuals (PMID:39702574). Similarly, a 7-month-old with the same genotype also has elevated NRE marker UA-HNAc(1S), but not in the range typically associated with MPS I (PMID:39702574) (Total 1.5 points, PM3). PP4 was applied based on the reported features of MPS I in some patients. The computational predictor REVEL gives a score of 0.774 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). When the variant was expressed in IDUA knock-out HEK293 cells, the relative specific activity (activity of IDUA/amount of IDUA protein) was 15% of wild type activity (3 times higher than the activity of the "pseudodeficiency" variant, p.Ala79Thr, which is clinically benign). However, the p.Leu526Pro IDUA protein exhibits impaired proteolytic processing on Western blot, and evidence of aggregation of native gel electrophoresis. Based on the relatively high activity, but abnormalities in processing and aggregation, neither PS3 nor BS3 is met. There is a ClinVar entry for this variant (Variation ID: 567566). In summary, currently, the clinical impact of p.Leu526Pro is unclear, particularly given the reports of some patients with a diagnosis of MPS I, and others with normal total GAG levels and reports of only mild elevations of dermatan and heparan sulfate (PMID:39702574, Greenwood Genetic Center). This could suggest that the variant has reduced penetrance; however additional data is required to fully understand the clinical impact of this variant. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PM3_Strong, PP3_Moderate, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 21, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802300/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:4
• Conservation: PhyloP100: 1.82
• Publications: 9 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: Uncertain_significance. The variant received 5 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1577T>C	p.Leu526Pro	missense	Exon 11 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.1181T>C	p.Leu394Pro	missense	Exon 10 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1665T>C		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1577T>C	p.Leu526Pro	missense	Exon 11 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1577T>C	p.Leu526Pro	missense	Exon 11 of 14	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.1684T>C		non_coding_transcript_exon	Exon 8 of 11

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151922 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000336 AC: 40 AN: 118962 AF XY: 0.000397

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: 0.000566

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 554 AN: 1370464 Hom.: 0 Cov.: 33 AF XY: 0.000413 AC XY: 279 AN XY: 676024

African (AFR) AF: 0.00 AC: 0 AN: 29958

American (AMR) AF: 0.0000575 AC: 2 AN: 34810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24590

East Asian (EAS) AF: 0.00 AC: 0 AN: 34522

South Asian (SAS) AF: 0.000526 AC: 41 AN: 77886

European-Finnish (FIN) AF: 0.0000299 AC: 1 AN: 33394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.000460 AC: 494 AN: 1074004

Other (OTH) AF: 0.000280 AC: 16 AN: 57138

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151922 Hom.: 0 Cov.: 33 AF XY: 0.000337 AC XY: 25 AN XY: 74204

African (AFR) AF: 0.0000484 AC: 2 AN: 41364

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67958

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000728 Hom.: 0

Bravo AF: 0.000234

ExAC AF: 0.000179 AC: 11

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	2	-	Mucopolysaccharidosis type 1 (4)
-	2	-	not provided (2)
1	-	-	Mucopolysaccharidosis, MPS-I-H/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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.99
MPC		0.97
ClinPred		0.26	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.98
Mutation Taster		=2/98	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: rs781136336; hg19: chr4-997185;