4-1002945-G-T

Variant names:

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

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>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

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, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1402+1G>T		splice_donor intron	N/A	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.1006+1G>T		splice_donor intron	N/A	NP_001350505.1
	IDUA	NR_110313.1		n.1490+1G>T		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1402+1G>T		splice_donor intron	N/A	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1402+1G>T		splice_donor intron	N/A	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1477+1G>T		splice_donor intron	N/A	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 33

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: 1 AN: 1209638 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 586796

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

American (AMR) AF: 0.0000980 AC: 1 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: 29166

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 AF: 0.00000658 AC: 1 AN: 151910 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis type 1 (3)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Uncertain	0.98
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.74	D
PhyloP100		3.5
Mutation Taster		=0/100	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398123254;

hg19: chr4-996733;