rs750496798

Positions:

• chr4-1002383-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3_Supporting PP3_Moderate PM1 PP4 PM2_Supporting PS3_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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1087C>T	p.Arg363Cys	missense_variant	8/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1087C>T	p.Arg363Cys	missense_variant	8/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1087C>T	p.Arg363Cys	missense_variant	8/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.1194C>T		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1143C>T		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000832 AC: 2 AN: 240448 Hom.: 0 AF XY: 0.00000764 AC XY: 1 AN XY: 130892

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 16, 2023

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. 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:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 27, 2023

- -

Hurler syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 12, 2018

- -

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;.
MutationTaster	Benign	1.0	D;D;D
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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs750496798; hg19: chr4-996171;