rs786200915

Variant names:

• chr4-1001700-C-CCTGCT
• rs786200915
• NM_000203.5:c.613_617dupTGCTC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.613_617dup (p.Glu207AlafsTer29) variant in IDUA is a frameshift 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). At least 8 probands with a diagnosis of MPS I have been reported with the variant. At least 3 individuals with severe MPS I were homozygous for the variant (PMIDs: 8664897, 29620724; PM3). The allelic data for compound heterozygous individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002011 (9/44746 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). 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, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256123/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: -1.02
• Publications: 6 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 11 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.613_617dupTGCTC	p.Glu207AlafsTer29	frameshift_variant	Exon 6 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.217_221dupTGCTC	p.Glu75AlafsTer29	frameshift_variant	Exon 5 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.613_617dupTGCTC	p.Glu207AlafsTer29	frameshift_variant	Exon 6 of 12		XP_047271606.1
IDUA	NR_110313.1	n.701_705dupTGCTC		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.613_617dupTGCTC	p.Glu207AlafsTer29	frameshift_variant	Exon 6 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000869 AC: 2 AN: 230064 AF XY: 0.00000789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1448012 Hom.: 0 Cov.: 34 AF XY: 0.00000555 AC XY: 4 AN XY: 720748

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

American (AMR) AF: 0.00 AC: 0 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39570

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110946

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:5 Other:1

Dec 10, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.613_617dup (p.Glu207AlafsTer29) variant in IDUA is a frameshift 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). At least 8 probands with a diagnosis of MPS I have been reported with the variant. At least 3 individuals with severe MPS I were homozygous for the variant (PMIDs: 8664897, 29620724; PM3). The allelic data for compound heterozygous individuals will be used in the assessment of the second variant and was not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002011 (9/44746 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). 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, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common pathogenic variant in Japan -

Jun 22, 2018

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.613_617dupTGCTC (p.Glu207AlafsX29) 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. The variant allele was found at a frequency of 8.8e-06 in 227460 control chromosomes (gnomAD). The variant, c.613_617dupTGCTC, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh_2017, Kwak_2016, Yamagishi_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kwak_2016). 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. -

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Glu207AlafsTer29 variant in IDUA has been reported in least 7 individuals with mucopolysaccharidosis (MPS) (PMID: 8664897, 27520059) and has been identified in 0.011% (2/17752) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786200915). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 207 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with MPS increases the likelihood that the p.Glu207AlafsTer29 variant is pathogenic (VariationID: 11922; PMID: 8664897). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function and the presence of the variant in combination with known pathogenic variants in individuals with MPS. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015). -

Jul 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs786200915, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8664897, 27520059, 29620724). This variant is also known as 704ins5. ClinVar contains an entry for this variant (Variation ID: 11921). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Glu207Alafs*29) 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). -

Hurler syndrome Pathogenic:2

Dec 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs786200915; hg19: chr4-995488;