rs727503967

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM3PM2_SupportingPP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1614del (p.His539ThrfsTer21) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/20 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 4 individuals with MPS I, with documented IDUA deficiency within the affected range in leukocytes (PMID:8213840, 15300847, 19396826, 35141277) and/or clinical features specific to MPS I including short stature, joint stiffness, progressive developmental decline, severe hepatosplenomegaly, systolic murmur, mitral valve defects, umbilical hernia, hirsutism, large tongue, corneal clouding (PMID:15300847, 19396826) (PP4). Of these individuals, at least 3 were compound heterozygous for the variant and another variant in IDUA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID:8213840, 15300847, 35141277, 2 or 3 patients; max 2 x 0.5 points), and c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID:25614311, 0.5 points). Another patient is compound heterozygous for the variant and c.1650+5G>A (PMID:19396826). The allelic data from this patient will be used in the classification of c.1650+5G>A and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001741 (2/1148676 alleles) in the NFE 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: 167191). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Moderate, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA234129/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

IDUA
NM_000203.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: -0.130

Publications

2 publications found

Variant links:

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

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.1614delG	p.His539ThrfsTer21	frameshift_variant	Exon 11 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.1218delG	p.His407ThrfsTer21	frameshift_variant	Exon 10 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1801delG	p.Ala601HisfsTer53	frameshift_variant	Exon 10 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1702delG		non_coding_transcript_exon_variant	Exon 11 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1614delG	p.His539ThrfsTer21	frameshift_variant	Exon 11 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

137732

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000123

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000242

GnomAD4 exome

AF:

0.00000721

AC:

AN:

1386478

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

684778

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31752

American (AMR)

AF:

0.00

AC:

AN:

36012

Ashkenazi Jewish (ASJ)

AF:

0.000239

AC:

AN:

25138

East Asian (EAS)

AF:

0.00

AC:

AN:

35994

South Asian (SAS)

AF:

0.00

AC:

AN:

80040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5120

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080694

Other (OTH)

AF:

0.0000518

AC:

AN:

57894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:5

Jan 10, 2024

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.His539Thrfs*21) 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). This variant is present in population databases (rs727503967, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8213840, 19396826). This variant is also known as delG1702. ClinVar contains an entry for this variant (Variation ID: 167191). For these reasons, this variant has been classified as Pathogenic. -

Sep 03, 2021

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.1614delG (p.His539ThrfsX21) 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 1.5e-05 in 137732 control chromosomes. c.1614delG has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Scott_1993, Vazna_2009). These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 03, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 22, 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.His539ThrfsTer21 variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 19396826, 8213840) and has been identified in 0.012% (1/8140) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 167191). 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 has also been reported in ClinVar (VariationID: 167191) as pathogenic by EGL Genetic Diagnostics and Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 539 and leads to a premature termination codon 21 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 combination with a reported pathogenic variant in an individual with MPS slightly increases the likelihood that the p.His539ThrfsTer21 variant is pathogenic (VariationID: 11909; VariationID: 8213840). The phenotype of an individual compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase protein activity, consistent with disease (PMID: 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function of the IDUA gene, the presence of the variant in combination with pathogenic variants, and the phenotype of an individual with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1, PM3_supporting, PM2_supporting, PP4 (Richards 2015). -

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.1614del (p.His539ThrfsTer21) variant in IDUA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/20 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 4 individuals with MPS I, with documented IDUA deficiency within the affected range in leukocytes (PMID: 8213840, 15300847, 19396826, 35141277) and/or clinical features specific to MPS I including short stature, joint stiffness, progressive developmental decline, severe hepatosplenomegaly, systolic murmur, mitral valve defects, umbilical hernia, hirsutism, large tongue, corneal clouding (PMID: 15300847, 19396826) (PP4). Of these individuals, at least 3 were compound heterozygous for the variant and another variant in IDUA, phase unconfirmed, that has been classified as pathogenic by the ClinGen LD VCEP including c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID: 8213840, 15300847, 35141277, 2 or 3 patients; max 2 x 0.5 points), and c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 25614311, 0.5 points). Another patient is compound heterozygous for the variant and c.1650+5G>A (PMID: 19396826). The allelic data from this patient will be used in the classification of c.1650+5G>A and is not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001741 (2/1148676 alleles) in the NFE 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: 167191). In summary, this variant meets the criteria to be classified as Pathogenic for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Moderate, PP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

not provided

Pathogenic:2

Apr 21, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hurler syndrome

Pathogenic:2

Nov 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 01, 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. -

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

Pathogenic:1

Apr 29, 2022

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

PhyloP100

-0.13

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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rs727503967

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over