rs3755954

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92642). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA145883/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.22 ( 3827 hom., cov: 34)

Exomes 𝑓: 0.23 ( 40947 hom. )

Consequence

IDUA
NM_000203.5 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:16

Conservation

PhyloP100: -0.107

Publications

19 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: Benign. The variant received -8 ACMG points.

BA1

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.352C>T	p.Leu118Leu	synonymous_variant	Exon 3 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.352C>T	p.Leu118Leu	synonymous_variant	Exon 3 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

33067

AN:

152108

Hom.:

3823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.0661

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.250

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.202

AC:

50493

AN:

250192

AF XY:

0.195

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.228

Gnomad ASJ exome

AF:

0.133

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.231

AC:

336889

AN:

1459400

Hom.:

40947

Cov.:

AF XY:

0.225

AC XY:

163665

AN XY:

726026

show subpopulations

African (AFR)

AF:

0.189

AC:

6333

AN:

33452

American (AMR)

AF:

0.226

AC:

10126

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.134

AC:

3501

AN:

26132

East Asian (EAS)

AF:

0.128

AC:

5073

AN:

39694

South Asian (SAS)

AF:

0.0723

AC:

6237

AN:

86244

European-Finnish (FIN)

AF:

0.242

AC:

12648

AN:

52190

Middle Eastern (MID)

AF:

0.0825

AC:

466

AN:

5648

European-Non Finnish (NFE)

AF:

0.252

AC:

279770

AN:

1110994

Other (OTH)

AF:

0.211

AC:

12735

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13186

26372

39557

52743

65929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.217

AC:

33093

AN:

152226

Hom.:

3827

Cov.:

AF XY:

0.213

AC XY:

15834

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.192

AC:

7960

AN:

41528

American (AMR)

AF:

0.211

AC:

3228

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

467

AN:

3472

East Asian (EAS)

AF:

0.152

AC:

788

AN:

5172

South Asian (SAS)

AF:

0.0668

AC:

323

AN:

4834

European-Finnish (FIN)

AF:

0.242

AC:

2566

AN:

10606

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.250

AC:

17004

AN:

67994

Other (OTH)

AF:

0.196

AC:

414

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1358

2716

4073

5431

6789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.233

Hom.:

11615

Bravo

AF:

0.218

Asia WGS

AF:

0.102

AC:

357

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.226

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

May 25, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mucopolysaccharidosis type 1

Benign:4

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000203.5:c.352C>T variant in IDUA is a synonymous (silent) variant (p.Leu118=). The highest population minor allele frequency in gnomAD v4.1.0 is 0.2517 (296774/1178988 alleles; 37458 homozygotes) in the European non-Finnish population, which is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for BA1 (>0.005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 92642). In summary, this variant meets the criteria to be classified as benign for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): BA1. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9700243, 12509712, 19396826) -

Mucopolysaccharidosis, MPS-I-H/S

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mucopolysaccharidosis, MPS-I-S

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hurler syndrome

Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

(source)

DANN

Benign

0.60

PhyloP100

-0.11

Mutation Taster

=297/3

polymorphism (auto)

(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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rs3755954

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