NM_000203.5:c.1360G>A

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.1360G>A variant in IDUA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 454 (p.Val454Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.3004 (19925/66322 alleles; 3158 homozygotes; Grpmax Filtering AF 95% confidence = 0.2969) in the South Asian 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: 92630). 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/CA145872/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.17 ( 2366 hom., cov: 33)

Exomes 𝑓: 0.16 ( 17534 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 1.15

Publications

27 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.1360G>A	p.Val454Ile	missense_variant	Exon 9 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.964G>A	p.Val322Ile	missense_variant	Exon 8 of 13		NP_001350505.1
IDUA	XM_047415650.1 link	c.1360G>A	p.Val454Ile	missense_variant	Exon 9 of 12		XP_047271606.1
IDUA	NR_110313.1 link	n.1448G>A		non_coding_transcript_exon_variant	Exon 9 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1360G>A	p.Val454Ile	missense_variant	Exon 9 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26206

AN:

151822

Hom.:

2370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.166

Gnomad EAS

AF:

0.201

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.152

Gnomad OTH

AF:

0.183

GnomAD2 exomes

AF:

0.203

AC:

7144

AN:

35220

AF XY:

0.219

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.0791

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.255

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.161

AC:

202361

AN:

1256844

Hom.:

17534

Cov.:

AF XY:

0.164

AC XY:

101139

AN XY:

615192

show subpopulations

African (AFR)

AF:

0.222

AC:

5512

AN:

24830

American (AMR)

AF:

0.0948

AC:

1507

AN:

15894

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

3211

AN:

19602

East Asian (EAS)

AF:

0.158

AC:

4397

AN:

27792

South Asian (SAS)

AF:

0.301

AC:

18483

AN:

61502

European-Finnish (FIN)

AF:

0.159

AC:

4962

AN:

31246

Middle Eastern (MID)

AF:

0.212

AC:

859

AN:

4044

European-Non Finnish (NFE)

AF:

0.152

AC:

154678

AN:

1020122

Other (OTH)

AF:

0.169

AC:

8752

AN:

51812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

9324

18648

27972

37296

46620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5896

11792

17688

23584

29480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.172

AC:

26203

AN:

151930

Hom.:

2366

Cov.:

AF XY:

0.173

AC XY:

12841

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.212

AC:

8807

AN:

41480

American (AMR)

AF:

0.124

AC:

1890

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.166

AC:

575

AN:

3470

East Asian (EAS)

AF:

0.201

AC:

1029

AN:

5118

South Asian (SAS)

AF:

0.299

AC:

1442

AN:

4820

European-Finnish (FIN)

AF:

0.144

AC:

1513

AN:

10540

Middle Eastern (MID)

AF:

0.229

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.152

AC:

10340

AN:

67902

Other (OTH)

AF:

0.182

AC:

384

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1124

2248

3371

4495

5619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.154

Hom.:

298

Bravo

AF:

0.170

TwinsUK

AF:

0.166

AC:

614

ALSPAC

AF:

0.159

AC:

614

ExAC

AF:

0.114

AC:

3158

Asia WGS

AF:

0.250

AC:

869

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 02, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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.1360G>A variant in IDUA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 454 (p.Val454Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.3004 (19925/66322 alleles; 3158 homozygotes; Grpmax Filtering AF 95% confidence = 0.2969) in the South Asian 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: 92630). 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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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. -

not provided

Benign:4

Feb 27, 2017

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 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12509712, 28649516) -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

3.8

(source)

DANN

Benign

0.47

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.62

T;.

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

L;.

PhyloP100

1.1

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.094

Sift

Benign

0.81

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0070

B;.

Vest4

0.016

MPC

0.16

ClinPred

0.0022

GERP RS

0.14

Varity_R

0.13

gMVP

0.15

Mutation Taster

=95/5

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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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