rs1553917209

Variant names:

• chr4-1002064-AC-A
• rs1553917209
• NM_000203.5:c.876delC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PP4_Moderate PM2_Supporting PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.876del (p.Asp292GlufsTer25) variant in IDUA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in two individuals with clinical features consistent with MPS I, one of whom also had documented laboratory values showing deficiency leukocyte IDUA activity and elevated urine GAGs prior to initiation of treatment with enzyme replacement therapy (PMID:35848209) (PP4). One of these individuals is compound heterozygous for the variant (labeled as 964del in the publication, using older numbering) and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908); the phase was not confirmed (PMID:7951228, 0.5 points). Another patient is compound heterozygous for the variant and c.1499A>G (p.Gln500Arg) (PMID:35848209). The allelic data from this patient will be used in the classification of p.Gln500Arg and is not included here to avoid circular logic. Total 0.5 points (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001280 (15/1172250 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 456720). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PP4, PM2_Supporting, PM3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658657370/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.0950

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: 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.
• 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.876delC	p.Asp292GlufsTer25	frameshift_variant	Exon 7 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.876delC	p.Asp292GlufsTer25	frameshift_variant	Exon 7 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1442384 Hom.: 0 Cov.: 34 AF XY: 0.00000978 AC XY: 7 AN XY: 715596

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: 0.0000136

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 02, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.876delC (p.Asp292GlufsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1205G>A (p.Trp402X), c.1210G>T (p.Glu404X), and c.1799delC (p.Ser600X)). The variant was absent in 204226 control chromosomes (gnomAD). c.876delC has been reported in the literature in an individual affected with Mucopolysaccharidosis Type 1 (Bunge_1994). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asp292Glufs*25) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with MPS I (PMID: 7951228; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 456720). For these reasons, this variant has been classified as Pathogenic. -

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.876del (p.Asp292GlufsTer25) variant in IDUA is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in two individuals with clinical features consistent with MPS I, one of whom also had documented laboratory values showing deficiency leukocyte IDUA activity and elevated urine GAGs prior to initiation of treatment with enzyme replacement therapy (PMID: 35848209) (PP4). One of these individuals is compound heterozygous for the variant (labeled as 964del in the publication, using older numbering) and a variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908); the phase was not confirmed (PMID: 7951228, 0.5 points). Another patient is compound heterozygous for the variant and c.1499A>G (p.Gln500Arg) (PMID: 35848209). The allelic data from this patient will be used in the classification of p.Gln500Arg and is not included here to avoid circular logic. Total 0.5 points (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001280 (15/1172250 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 456720). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0.): PVS1, PP4, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Inborn genetic diseases Pathogenic:1

Jul 20, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 13, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8680403, 7951228) -

Hurler syndrome Pathogenic:1

Sep 06, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This IDUA variant is absent from large population datasets. A single submitter in ClinVar classifies this variant as pathogenic. This frameshift variant results in a premature stop codon in exon 7 likely leading to nonsense-mediated decay and lack of protein production. This variant is considered likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1553917209; hg19: chr4-995852;