rs1553917209

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 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:8
• Conservation: PhyloP100: -0.0950
• Publications: 1 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: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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.

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.876delC	p.Asp292GlufsTer25	frameshift	Exon 7 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.480delC	p.Asp160GlufsTer25	frameshift	Exon 6 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.964delC		non_coding_transcript_exon	Exon 7 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.876delC	p.Asp292GlufsTer25	frameshift	Exon 7 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.876delC	p.Asp292GlufsTer25	frameshift	Exon 7 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.951delC	p.Asp317GlufsTer25	frameshift	Exon 8 of 15	ENSP00000632448.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 41232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 38990

South Asian (SAS) AF: 0.00 AC: 0 AN: 82974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1104270

Other (OTH) AF: 0.0000167 AC: 1 AN: 59748

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
2	-	-	not provided (2)
1	-	-	Hurler syndrome (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.095
Mutation Taster		=1/199	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: rs1553917209; hg19: chr4-995852;