rs121965023

Variant names:

• chr4-1002117-C-T
• rs121965023
• NM_000203.5:c.928C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_Supporting PP4 PM3_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.928C>T (p.Gln310Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR product showed a "doublet" with an upper band slightly larger than the normal band (505bp). Part of the mRNA was spliced from intron 5 to include 28nt of intronic sequence, indicating use of a cryptic splice site. This alternative splicing was said to create a frameshift and an open reading frame until exon 9. Since RT-PCR appears to show a near complete proportion of alternatively spliced transcript, the strength of PVS1 was reduced by 1 level to strong (PVS1_Strong; PMID:8328452). This variant has been detected in at least 1 individual with MPS I. This individual was homozygous for the variant (PMID:8328452; PM3_Supporting). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex, corneal opacities, hepatosplenomegaly, and arthropathy (PMID:8328452; PP4). The highest population minor allele frequency in gnomAD v4.0. is 0.0000008630 (1/1158762 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). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 11915, 0 star review status) with 1 submitter classifying the variant as pathogenic; however this submitter is OMIM. 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 Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1_Strong, PM3_Supporting, PP4, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 3, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256115/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 3.71
• Publications: 7 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 7 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.928C>T	p.Gln310*	stop_gained	Exon 7 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.532C>T	p.Gln178*	stop_gained	Exon 6 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.928C>T	p.Gln310*	stop_gained	Exon 7 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1016C>T		non_coding_transcript_exon_variant	Exon 7 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.928C>T	p.Gln310*	stop_gained	Exon 7 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418258 Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1 AN XY: 701350

African (AFR) AF: 0.00 AC: 0 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 37634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 37650

South Asian (SAS) AF: 0.00 AC: 0 AN: 80900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090726

Other (OTH) AF: 0.00 AC: 0 AN: 58786

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000727 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:1

Mar 03, 2025

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.928C>T (p.Gln310Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. However, RT-PCR product showed a "doublet" with an upper band slightly larger than the normal band (505bp). Part of the mRNA was spliced from intron 5 to include 28nt of intronic sequence, indicating use of a cryptic splice site. This alternative splicing was said to create a frameshift and an open reading frame until exon 9. Since RT-PCR appears to show a near complete proportion of alternatively spliced transcript, the strength of PVS1 was reduced by 1 level to strong (PVS1_Strong; PMID: 8328452). This variant has been detected in at least 1 individual with MPS I. This individual was homozygous for the variant (PMID: 8328452; PM3_Supporting). At least 1 patient with this variant had clinical features specific to MPS I including dysostosis multiplex, corneal opacities, hepatosplenomegaly, and arthropathy (PMID: 8328452; PP4). The highest population minor allele frequency in gnomAD v4.0. is 0.0000008630 (1/1158762 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). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 11915, 0 star review status) with 1 submitter classifying the variant as pathogenic; however this submitter is OMIM. 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 Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PVS1_Strong, PM3_Supporting, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 3, 2025) -

Hurler syndrome Pathogenic:1

Aug 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		3.7
Vest4		0.86
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121965023; hg19: chr4-995905;