4-1002945-G-T

Position:

chr4-1002945-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4PM3PM2_SupportingPVS1_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

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:

IDUA (HGNC:):

IDUA links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.1402+1G>T		splice_donor_variant, intron_variant		ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.1402+1G>T		splice_donor_variant, intron_variant		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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000980

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151910

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	ClinVar contains an entry for this variant (Variation ID: 1323099). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type I (PMID: 21480867). This variant is not present in population databases (gnomAD no frequency). 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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 26, 2022	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. -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 17, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.74

GERP RS

4.3

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

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