chr4-1002325-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM3_StrongPP4PM2_Supporting

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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: -0.0490

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1029C>G	p.Tyr343*	stop_gained	Exon 8 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1136C>G		non_coding_transcript_exon_variant	Exon 5 of 11	5
IDUA	ENST00000652070.1 link	n.1085C>G		non_coding_transcript_exon_variant	Exon 7 of 13

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248154

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134754

show subpopulations

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 SAS 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.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:3

Nov 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr343*) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (rs764196171, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8019572, 9391892, 31298590). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550474). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 06, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 05, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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) -

not provided

Pathogenic:1

Nov 17, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome

Pathogenic:1

Jan 26, 2017

Counsyl

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

0.50

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Benign

0.93

Eigen

Benign

-0.73

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.43

Vest4

0.83

GERP RS

-7.4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over