rs764196171

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-1002325-C-A
• chr4-1002325-C-G
• chr4-1002325-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1029C>A (p.Tyr343Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 8 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes and urinary GAGs expressed as heparan and dermatan sulfate GAG elevation above normal range (PP4; PMID:35141277). This variant has been detected in at least 2 individuals with MPS I. Of those individuals, both were compound heterozygous for the variant and a pathogenic variant (c.208C>T p (Gln70Ter)) and neither of those were confirmed in trans (PM3; PMID:35141277). This variant is absent in gnomAD v4.1.0. (PM2_Supporting). To our knowledge, the results of functional assays have not been reported for this variant. In summary, this variant meets the criteria to be classified as 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): PVS1, PP4, PM3, 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/CA356984/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 34)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• 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: 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: Pathogenic. The variant received 12 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>A	p.Tyr343*	stop_gained	Exon 8 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.633C>A	p.Tyr211*	stop_gained	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1117C>A		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>A	p.Tyr343*	stop_gained	Exon 8 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1029C>A	p.Tyr343*	stop_gained	Exon 8 of 14	ENSP00000247933.4
	IDUA	ENST00000962389.1		c.1104C>A	p.Tyr368*	stop_gained	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Benign	0.93
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.42	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)		0.090		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: rs764196171; hg19: chr4-996113;