chr4-1001695-C-A

Variant names:

• chr4-1001695-C-A
• rs1033313360
• NM_000203.5:c.606C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.606C>A (p.Tyr202Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, all 3 were compound heterozygous for the variant and a pathogenic variant (c.979G>C p.A327P; c.208C>T p.Q70X; c.1205G>A p.W402X) and none of those were confirmed in trans (PMIDs: 27392569, 22976768, clinical lab; PM3). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex and arthropathy (PMID:27392569; PP4). The highest population minor allele frequency in gnomAD v4.0 is 0.000005089 (6/1179008 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). 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: 552333, 2 star review status) with 5 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as 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, PM3, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 6, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355961907/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.443
• Publications: 3 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: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.606C>A	p.Tyr202*	stop_gained	Exon 6 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.210C>A	p.Tyr70*	stop_gained	Exon 5 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.606C>A	p.Tyr202*	stop_gained	Exon 6 of 12		XP_047271606.1
IDUA	NR_110313.1	n.694C>A		non_coding_transcript_exon_variant	Exon 6 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.606C>A	p.Tyr202*	stop_gained	Exon 6 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000433 AC: 1 AN: 230974 AF XY: 0.00000787

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000946

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1448430 Hom.: 0 Cov.: 34 AF XY: 0.00000416 AC XY: 3 AN XY: 720944

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.0000238 AC: 1 AN: 41976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110994

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000325 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Jan 27, 2022

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.606C>A (p.Tyr202X) 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. The variant allele was found at a frequency of 4.3e-06 in 230974 control chromosomes (gnomAD). c.606C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (e.g. Matte_2003, Pollard_2013, Ghosh_2017). Two ClinVar submitters (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 07, 2023

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.Tyr202*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552333). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 12559846). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Jan 21, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 06, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.606C>A (p.Tyr202Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 6 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, all 3 were compound heterozygous for the variant and a pathogenic variant (c.979G>C p.A327P; c.208C>T p.Q70X; c.1205G>A p.W402X) and none of those were confirmed in trans (PMIDs: 27392569, 22976768, clinical lab; PM3). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex and arthropathy (PMID: 27392569; PP4). The highest population minor allele frequency in gnomAD v4.0 is 0.000005089 (6/1179008 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). 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: 552333, 2 star review status) with 5 submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as 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, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 6, 2025) -

Hurler syndrome Pathogenic:2

Jun 07, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 29, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

Mar 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.30	N
PhyloP100		-0.44
Vest4		0.73
ClinPred		0.97	D
GERP RS		-4.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1033313360; hg19: chr4-995483;