4-1002945-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3PM2_SupportingPP4PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5: c.1402+1G>T variant in IDUA occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9 (there are 14 exons in IDUA), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been identified in three patients with clinical features of severe MPS 1 including including cognitive delay, visual impairment, joint disease, hepatosplenomegaly, hernia, cardiac disease, and/or respiratory disease. Two of these patients also had documented IDUA deficiency within the affected range in leukocytes (PMID:21480867, 27896125). An additional patient was identified by newborn screening with confirmatory deficient IDUA, elevated urine GAGs, and was treated with ERT and HSCT (PMID:37516270) (PP4). Of these individuals, two were homozygous for the variant (PMID:21480867, 27896125), and one individual was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter), phase unknown (ClinVar Variation ID: 11908) (PMID:37516270). Another individual is compound heterozygous for the variant and p.Ala79Val; the allelic data for this individual will be used in the classification of p.Ala79Val and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003924 (1/25482; 0 homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Additional variants at this splice donor site have been identified in individuals with features of MPS 1, including c.1402+1G>A (PMID:27146977). There is a ClinVar entry for this variant (Variation ID: 1323099. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_Strong, PP4, PM3, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA355964387/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 3.51

Publications

1 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: Likely_pathogenic. The variant received 8 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	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1402+1G>T	splice_donor_variant, intron_variant	Intron 9 of 13	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.1006+1G>T	splice_donor_variant, intron_variant	Intron 8 of 12		NP_001350505.1
IDUA	NR_110313.1 link	n.1490+1G>T	splice_donor_variant, intron_variant	Intron 9 of 13
IDUA	XM_047415650.1 link	c.1402+1G>T	splice_donor_variant, intron_variant	Intron 9 of 11		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.1402+1G>T		splice_donor_variant, intron_variant	Intron 9 of 13	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

AF:

8.27e-7

AC:

AN:

1209638

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

586796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23674

American (AMR)

AF:

0.0000980

AC:

AN:

10208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16938

East Asian (EAS)

AF:

0.00

AC:

AN:

27262

South Asian (SAS)

AF:

0.00

AC:

AN:

51490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

996884

Other (OTH)

AF:

0.00

AC:

AN:

49818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:3

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000203.5: c.1402+1G>T variant in IDUA occurs within the canonical splice donor site of intron 9. It is predicted to cause skipping of biologically-relevant-exon 9 (there are 14 exons in IDUA), resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been identified in three patients with clinical features of severe MPS 1 including including cognitive delay, visual impairment, joint disease, hepatosplenomegaly, hernia, cardiac disease, and/or respiratory disease. Two of these patients also had documented IDUA deficiency within the affected range in leukocytes (PMID: 21480867, 27896125). An additional patient was identified by newborn screening with confirmatory deficient IDUA, elevated urine GAGs, and was treated with ERT and HSCT (PMID: 37516270) (PP4). Of these individuals, two were homozygous for the variant (PMID: 21480867, 27896125), and one individual was compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter), phase unknown (ClinVar Variation ID: 11908) (PMID: 37516270). Another individual is compound heterozygous for the variant and p.Ala79Val; the allelic data for this individual will be used in the classification of p.Ala79Val and is not included here to avoid circular logic (PM3). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00003924 (1/25482; 0 homozygotes) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Additional variants at this splice donor site have been identified in individuals with features of MPS 1, including c.1402+1G>A (PMID: 27146977). There is a ClinVar entry for this variant (Variation ID: 1323099. In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1_Strong, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Jan 26, 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.1402+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 7392 control chromosomes (gnomAD and publication data). c.1402+1G>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (Wang_2012, Pineda_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 9 of the IDUA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type I (PMID: 21480867). ClinVar contains an entry for this variant (Variation ID: 1323099). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Nov 17, 2021

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000203.3(IDUA):c.1402+1G>T is a canonical splice variant classified as pathogenic in the context of mucopolysaccharidosis type I. c.1402+1G>T has been observed in cases with relevant disease (PMID: 21480867, 27896125). Functional assessments of this variant are not available in the literature. c.1402+1G>T has not been observed in population frequency databases. In summary, NM_000203.3(IDUA):c.1402+1G>T is a canonical splice variant variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:1

Mar 05, 2021

Revvity Omics, Revvity

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

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.74

PhyloP100

3.5

GERP RS

4.3

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DL_spliceai

1.0

Position offset: -1

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over