chr4-1004082-TC-T

Variant names:

• chr4-1004082-TC-T
• rs398123258
• NM_000203.5:c.1799delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PP4 PM3_Strong PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.1799del (p.Ser600Ter) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed. (PVS1_Moderate). At least 5 patients with this variant have been reported with this variant, four with documented clinical features consistent with MPS 1 and IDUA deficiency within the affected range in leukocytes; two had mildly elevated GAGs, one after receiving HSCT and one was possibly on treatment (clinical laboratory data) (PP4). Three patients were compound heterozygous for the variant and a variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (c.208C>T (p.Gln70Ter), c.1728-2A>G, and c.1898C>G (p.Ser633Trp)) and none of those were confirmed in trans (clinical diagnostic lab). At least two individuals were homozygous for the variant PMID:22976768, clinical diagnostic lab) (PM3_Strong). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 92636). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1_Moderate, PP4, PM3_Strong, 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/CA220505/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.46
• Publications: 2 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: Likely_pathogenic. The variant received 8 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.1799delC	p.Ser600fs	frameshift	Exon 13 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1403delC	p.Ser468fs	frameshift	Exon 12 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1891delC		non_coding_transcript_exon	Exon 13 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1799delC	p.Ser600fs	frameshift	Exon 13 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1799delC	p.Ser600fs	frameshift	Exon 13 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1874delC	p.Ser625fs	frameshift	Exon 14 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123258; hg19: chr4-997870;