NM_000203.5:c.1087C>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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1087C>T	p.Arg363Cys	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.691C>T	p.Arg231Cys	missense_variant	Exon 7 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1087C>T	p.Arg363Cys	missense_variant	Exon 8 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1175C>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.1087C>T	p.Arg363Cys	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1087C>T	p.Arg363Cys	missense_variant	Exon 8 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1194C>T		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1	n.1143C>T		non_coding_transcript_exon_variant	Exon 7 of 13

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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)

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 363 of the IDUA protein (p.Arg363Cys). This variant is present in population databases (rs750496798, gnomAD 0.002%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847). ClinVar contains an entry for this variant (Variation ID: 557205). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 15300847). This variant disrupts the p.Arg363 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21734815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not provided Pathogenic:2

Sep 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies found this variant is associated with significantly reduced IDUA activity and protein expression (PMID: 15300847); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24480078, 24036510, 28676128, 21734815, 15300847)

Dec 27, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hurler syndrome Uncertain:1

Mar 12, 2018

Counsyl

Significance: Uncertain significance

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.

Computational scores

Source: dbNSFP v4.3

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;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
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;