4-1002945-G-A

Variant names:

• chr4-1002945-G-A
• rs398123254
• NM_000203.5:c.1402+1G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3 PM2_Supporting PP4 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1402+1G>A variant in IDUA occurs within the canonical splice donor site of intron 9. While the effect of this change has not been proven experimentally, it is predicted to cause skipping of biologically-relevant-exon 9 out of 14 total exons, resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been detected in at least two individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and c.502G>T p.(Gly168Ter), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID:33301762). The other individual was homozygous for the variant (PMID:27146977) (PM3). These two patients had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including coarse facies, hepatosplenomegaly, corneal opacity, recurrent infections, intellectual disability, hernia, and/or cardiomegaly, cardiomyopathy, and dysostosis multiplex (PP4)(PMIDs: 33301762, 27146977). This variant is absent in gnomAD v4.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555490). In summary, this variant meets the criteria to be classified as likely 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 1.0.0): (PVS1_Strong, PM3, PP4, 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/CA355964379/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IDUA NM_000203.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 3.51
• Publications: 1 publications found

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

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1402+1G>A		splice_donor_variant, intron_variant	Intron 9 of 13	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1006+1G>A		splice_donor_variant, intron_variant	Intron 8 of 12		NP_001350505.1
IDUA	NR_110313.1	n.1490+1G>A		splice_donor_variant, intron_variant	Intron 9 of 13
IDUA	XM_047415650.1	c.1402+1G>A		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	c.1402+1G>A		splice_donor_variant, intron_variant	Intron 9 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1209636 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 586794

African (AFR) AF: 0.00 AC: 0 AN: 23674

American (AMR) AF: 0.00 AC: 0 AN: 10208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16938

East Asian (EAS) AF: 0.00 AC: 0 AN: 27262

South Asian (SAS) AF: 0.00 AC: 0 AN: 51490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4198

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996884

Other (OTH) AF: 0.00 AC: 0 AN: 49818

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Dec 05, 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>A variant in IDUA occurs within the canonical splice donor site of intron 9. While the effect of this change has not been proven experimentally, it is predicted to cause skipping of biologically-relevant-exon 9 out of 14 total exons, resulting in an in-frame deletion of amino acids 397-467 which represents >10% of the protein (PVS1_Strong). This variant has been detected in at least two individuals with MPS I. Of those individuals, one was compound heterozygous for the variant and c.502G>T p.(Gly168Ter), which is classified as pathogenic by the ClinGen Lysosomal Diseases VCEP; it is unknown if these variants were confirmed in trans (PMID: 33301762). The other individual was homozygous for the variant (PMID: 27146977) (PM3). These two patients had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including coarse facies, hepatosplenomegaly, corneal opacity, recurrent infections, intellectual disability, hernia, and/or cardiomegaly, cardiomyopathy, and dysostosis multiplex (PP4)(PMIDs: 33301762, 27146977). This variant is absent in gnomAD v4.0. (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 555490). In summary, this variant meets the criteria to be classified as likely 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 1.0.0): (PVS1_Strong, PM3, PP4, PM2_Supporting). (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024). -

Hurler syndrome Pathogenic:1

Dec 06, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

Mar 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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	D
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.58	D
PhyloP100		3.5
GERP RS		4.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Other links and lift over

dbSNP: rs398123254; hg19: chr4-996733;