4-1002383-C-T

Variant names:

• chr4-1002383-C-T
• rs750496798
• NM_000203.5:c.1087C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2_Supporting PS3_Moderate PP4 PM3_Supporting PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1087C>T variant in IDUA is predicted to result in the substitution of arginine by cysteine at amino acid 363 (p.Arg363Cys). This variant alters amino acid Arg363, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMIDs: 23959878, 24036510) (PM1). When the variant was expressed in CHO cells, no IDUA activity was detected, and synthesis and processing was abnormal (PMID:15300847). The computational predictor REVEL gives a score of 0.845 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). Two patients with the variant have clinical symptoms consistent with MPS1 and one has "undetectable" IDUA activity (PMID:15300847, 32781600). One of these patients is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP with unconfirmed phase, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID:32781600). The other patient is compound heterozygous for the variant and c.1804T>A (p.Phe602Ile) (PMID:15300847). The allelic data from this patient will be used in the classification of p.Phe602Ile and is not included here to avoid circular logic (PM3_Supporting). Another variant at the same amino acid position, c.1088G>A (p.Arg363His) has been identified in an individual with MPS 1 (PMID:21734815). This variant has not yet been classified by the ClinGen LD VCEP. There is a Clinvar entry for this variant (Variation ID: 557205). In summary, this variant meet the criteria to be classified as likely pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen LD VCEP (Specifications Version 1.0.0): PM1, PP3_Moderate, PS3_Supporting, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802184/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 2.53
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: 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.1087C>T	p.Arg363Cys	missense	Exon 8 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.691C>T	p.Arg231Cys	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1175C>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.1087C>T	p.Arg363Cys	missense	Exon 8 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1087C>T	p.Arg363Cys	missense	Exon 8 of 14	ENSP00000247933.4
	IDUA	ENST00000962389.1		c.1162C>T	p.Arg388Cys	missense	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000832 AC: 2 AN: 240448 AF XY: 0.00000764

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: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457760 Hom.: 0 Cov.: 35 AF XY: 0.00000552 AC XY: 4 AN XY: 725008

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39532

South Asian (SAS) AF: 0.00 AC: 0 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110516

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (2)
2	-	-	not provided (2)
-	1	-	Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.88
Mutation Taster		=5/95	disease causing

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: rs750496798; hg19: chr4-996171;