4-1002325-C-G

Variant names:

• chr4-1002325-C-G
• rs764196171
• NM_000203.5:c.1029C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4 PM2_Supporting PM3_Strong PVS1

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.1029C>G (p.Tyr343Ter) variant is a nonsense variant observed to cause a premature stop codon in biologically relevant exon 8 (out of 14), leading to nonsense-mediated decay in the IDUA gene in which loss-of-function is an established disease mechanism. Expression of the variant in COS-7 cells showed 1.1% of normal IDUA activity (PMID:9391892) (PVS1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/15956 alleles) in the African population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). This variant has been detected in at least 3 individuals with MPS I. Of those individuals, 2 were heterozygous for the variant and a pathogenic or likely pathogenic variant (variants are: c.208C>T (p.Gln70Ter), c.3G>A (p.Met1?)), and one of those was confirmed in trans (PMIDs: 15081804, 9391892, 8019572) (PM3_Strong). At least 1 patient with this variant had undetectable IDUA activity in skin fibroblasts (PP4) (PMID:15081804). There is a ClinVar entry for this variant (Variation ID: 550474). In summary, this variant meets the criteria to be classified as pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PVS1, PM2_Supporting, PM3_Strong, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802166/MONDO:0001586/010

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: -0.0490
• Publications: 9 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: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Pathogenic. The variant received 14 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.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.633C>G	p.Tyr211*	stop_gained	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1117C>G		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1104C>G	p.Tyr368*	stop_gained	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248154 AF XY: 0.00000742

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74398

African (AFR) AF: 0.0000241 AC: 1 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis type 1 (3)
2	-	-	not provided (2)
1	-	-	Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	35
DANN	Benign	0.93
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.43	N
PhyloP100		-0.049
Vest4		0.83
GERP RS		-7.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 1

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

Other links and lift over

dbSNP: rs764196171; hg19: chr4-996113;