NM_000203.5:c.1898C>G

Variant names:

• chr4-1004329-C-G
• rs886043347
• NM_000203.5:c.1898C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PM2_Supporting PP4 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1898C>G variant in IDUA is a missense variant predicted to cause substitution of serine by tryptophan at amino acid 633 (p.Ser633Trp). This variant has been detected in at least 4 individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (phase not confirmed, 0.5 points, PMID:24798265). Three individuals were homozygous for the variant (max 1 point, PMIDs: 24798265, 33389473). Total: 1.5 points (PM3). One of these patients had documented IDUA deficiency within the affected range in dried blood spot and clinical features specific to MPS I including dysostosis multiplex, arthropathy, and corneal involvement (PMID:PMID: 33389473) (PP4). The computational predictor REVEL gives a score of 0.871 which is above the threshold of 0.773 (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60010 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). Another variant at the same amino acid position, p.Ser633Leu, has been reported in individuals with MPS I (PMID:11735025, 21480867. This variant has not yet been classified by the ClinGen LD VCEP, therefore, PM5 was not applied. There is a ClinVar entry for this variant (Variation ID: 286242). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PM3, PP3_Moderate, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10605410/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 4.17
• Publications: 17 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 6 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1898C>G	p.Ser633Trp	missense	Exon 14 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.1502C>G	p.Ser501Trp	missense	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1990C>G		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1898C>G	p.Ser633Trp	missense	Exon 14 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1898C>G	p.Ser633Trp	missense	Exon 14 of 14	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.2009C>G		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 249054 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459632 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 633 of the IDUA protein (p.Ser633Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 24798265, 33389473). ClinVar contains an entry for this variant (Variation ID: 286242). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. This variant disrupts the p.Ser633 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Ser633Trp variant in IDUA has been reported in at least 4 individuals with mucopolysaccharidosis (MPS) (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397) and has been identified in 0.003% (1/34546) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043347). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as pathogenic by EGL Genetic Diagnostics (Variation ID: 286242). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Ser633Leu, has been reported pathogenic in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 16438163, 28752568, 11735025, 2448007; VariationID: 556406). The p.Ser633Trp variant is located in a region of IDUA that is important for protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 24480078). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on a-L-Iduronidase activity being <1% of normal, consistent with disease (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). The presence of this variant in at least 3 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Ser633Trp variant is pathogenic (VariationID: 11908; PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3, PM1_supporting, PP4 (Richards 2015).

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.1898C>G variant in IDUA is a missense variant predicted to cause substitution of serine by tryptophan at amino acid 633 (p.Ser633Trp). This variant has been detected in at least 4 individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (phase not confirmed, 0.5 points, PMID: 24798265). Three individuals were homozygous for the variant (max 1 point, PMIDs: 24798265, 33389473). Total: 1.5 points (PM3). One of these patients had documented IDUA deficiency within the affected range in dried blood spot and clinical features specific to MPS I including dysostosis multiplex, arthropathy, and corneal involvement (PMID: PMID: 33389473) (PP4). The computational predictor REVEL gives a score of 0.871 which is above the threshold of 0.773 (PP3_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003333 (2/60010 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). Another variant at the same amino acid position, p.Ser633Leu, has been reported in individuals with MPS I (PMID: 11735025, 21480867. This variant has not yet been classified by the ClinGen LD VCEP, therefore, PM5 was not applied. There is a ClinVar entry for this variant (Variation ID: 286242). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.1.0): PM3, PP3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024).

not provided Pathogenic:3

Feb 10, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 15, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 11735025, 24480078, 24798265, 32235807, 33389473)

Mar 14, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Mar 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.97
MPC		0.89
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.99
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: rs886043347; hg19: chr4-998117;