4-1004011-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PP4PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1728-1G>C variant in IDUA occurs within the canonical splice acceptor site of intron 12. It is predicted to cause skipping of biologically-relevant exon 13 out of 14, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 3 patients with this variant had documented IDUA deficiency within the affected range and urinary GAG elevation above normal range (PP4; PMID:31194252). This variant has been detected in at least 2 individuals with MPS I. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant (Q70X; W402X) and neither of those were confirmed in trans (PM3; PMID:31194252). The highest population minor allele frequency in gnomAD v4.0. is 0.00001612 (19/1178792 alleles) in the European (non-Finnish) 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 IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0): PVS1, PP4, 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/CA355965306/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

IDUA
NM_000203.5 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 1.84

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.1728-1G>C		splice_acceptor_variant, intron_variant	Intron 12 of 13	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1728-1G>C	splice_acceptor_variant, intron_variant	Intron 12 of 13	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1728-1G>C	splice_acceptor_variant, intron_variant	Intron 12 of 13	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1839-1G>C	splice_acceptor_variant, intron_variant	Intron 9 of 10	5
IDUA	ENST00000652070.1 link	n.1784-1G>C	splice_acceptor_variant, intron_variant	Intron 11 of 12

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251038

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460418

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150260

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73166

show subpopulations

Gnomad4 AFR

AF:

0.0000245

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:3Other:1

Apr 05, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 07-30-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 12 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: 22976768, 28752568). ClinVar contains an entry for this variant (Variation ID: 556064). 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. -

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.1728-1G>C variant in IDUA occurs within the canonical splice acceptor site of intron 12. It is predicted to cause skipping of biologically-relevant exon 13 out of 14, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 3 patients with this variant had documented IDUA deficiency within the affected range and urinary GAG elevation above normal range (PP4; PMID: 31194252). This variant has been detected in at least 2 individuals with MPS I. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant (Q70X; W402X) and neither of those were confirmed in trans (PM3; PMID: 31194252). The highest population minor allele frequency in gnomAD v4.0. is 0.00001612 (19/1178792 alleles) in the European (non-Finnish) 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 IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0): PVS1, PP4, PM3, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Nov 18, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000203.3(IDUA):c.1728-1G>C is a a canonical splice variant classified as likely pathogenic in the context of mucopolysaccharidosis type I. c.1728-1G>C has been observed in cases with relevant disease (PMID: 31194252). Functional assessments of this variant are not available in the literature. c.1728-1G>C has not been observed in population frequency databases. In summary, NM_000203.3(IDUA):c.1728-1G>C is a canonical splice 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

Dec 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28752568, 22976768) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.74

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.74

Position offset: -25

DS_AL_spliceai

0.61

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over