rs398123258

Positions:

• chr4-1004082-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4 PM2_Supporting 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

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1799delC	p.Ser600fs	frameshift_variant	13/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1799delC	p.Ser600fs	frameshift_variant	13/14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1799delC	p.Ser600fs	frameshift_variant	13/14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1910delC		non_coding_transcript_exon_variant	10/11	5
IDUA	ENST00000652070.1	n.1855delC		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IDUA protein in which other variant(s) (p.Arg628*) have been determined to be pathogenic (PMID: 11735025, 16435195; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 92636). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis (PMID: 22976768). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser600*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 54 amino acid(s) of the IDUA protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The IDUA c.1799delC (p.Ser600Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent IDUA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120794 control chromosomes. This variant has been reported homozygously in one mucopolysaccharidosis patient, and variant showed zero enzyme activity (Pollard_IUDA_IJMD_2013). In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 22, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2016	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123258; hg19: chr4-997870;