4-1004286-C-T

Variant names:

• chr4-1004286-C-T
• rs121965031
• NM_000203.5:c.1855C>T

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3 PM2_Supporting PP4 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1855C>T (p.Arg619Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed. (PVS1_Moderate; PMID:24480078). At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes or plasma, and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PP4). This variant has been detected in at least 12 individuals with MPS I. Of those individuals, 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (Variants: 1163C>G (p.Thr388Arg), 1598C>G (p.Pro533Arg), 1205G>A (p.Trp402Ter), 386-2A>G, 208C>T (p.Gln70Ter)) and none of those were confirmed in trans (PMIDs: 28752568, 11735025). 6 individuals were homozygous for the variant (PMID:28752568, PMID:27146977) (PM3_very strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002881 (34/1179960 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: 280976, 2 star review status) with 6 submitters classifying the variant as pathogenic. 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 1.0.0): PM3_very strong, PVS1_moderate, PP4, 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/CA2802455/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.378
• Publications: 16 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 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1855C>T	p.Arg619*	stop_gained	Exon 14 of 14	NP_000194.2
	IDUA	NM_001363576.1		c.1459C>T	p.Arg487*	stop_gained	Exon 13 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1947C>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1855C>T	p.Arg619*	stop_gained	Exon 14 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.1855C>T	p.Arg619*	stop_gained	Exon 14 of 14	ENSP00000247933.4
	IDUA	ENST00000514698.5	TSL:5	n.1966C>T		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151986 Hom.: 0 Cov.: 32

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247950 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

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: 0.00000891

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1458628 Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15 AN XY: 725780

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151986 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67984

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

Alfa AF: 0.0000240 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:5

Feb 05, 2024

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.Arg619*) in the IDUA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the IDUA protein. This variant is present in population databases (rs121965031, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (MPS I) (PMID: 11735025, 27146977, 28752568). ClinVar contains an entry for this variant (Variation ID: 280976). 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.

Jul 02, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDUA c.1855C>T (p.Arg619X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.5e-05 in 119432 control chromosomes (ExAC). The variant, c.1855C>T, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 with limited to no IDUA enzyme activity detected (Beesley_2001, Uttarilli_2016). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Jul 22, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.1855C>T (p.Arg619Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed. (PVS1_Moderate; PMID: 24480078). At least 4 patients with this variant had documented IDUA deficiency within the affected range in leukocytes or plasma, and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PP4). This variant has been detected in at least 12 individuals with MPS I. Of those individuals, 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (Variants: 1163C>G (p.Thr388Arg), 1598C>G (p.Pro533Arg), 1205G>A (p.Trp402Ter), 386-2A>G, 208C>T (p.Gln70Ter)) and none of those were confirmed in trans (PMIDs: 28752568, 11735025). 6 individuals were homozygous for the variant (PMID: 28752568, PMID: 27146977) (PM3_very strong). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00002881 (34/1179960 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: 280976, 2 star review status) with 6 submitters classifying the variant as pathogenic. 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 1.0.0): PM3_very strong, PVS1_moderate, PP4, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024)

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg619Ter variant in IDUA has been reported in at least 12 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 11735025, 27146977) and has been identified in 0.001% (1/112290) of European (non-Finnish) chromosomes by the the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965031). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 280976) as pathogenic by EGL Genetic Diagnostics and Counsyl. This nonsense variant leads to a premature termination codon at position 619. This alteration occurs in the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The phenotype of individuals homozygous for this variant is highly specific for MPS based on very low alpha-L-iduronidase activity consistent with disease (PMID: 27146977). The presence of this variant in 6 affected homozygotes and in combination with reported pathogenic variants in at least 5 individuals with MPS increases the likelihood that the p.Arg619Ter variant is pathogenic (VariationID: 11908, 11909, 11910, 496834; PMID: 28752568, 11735025, 27146977). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it results in a truncated protein, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PM2, PP4 (Richards 2015).

not provided Pathogenic:3

Mar 22, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 35 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11735025, 33301762, 28752568, 27146977)

Jul 03, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hurler syndrome Pathogenic:2

May 05, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 23, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous nonsense variant in exon 14 of the IDUA gene that results in a stop codon and premature truncation of the protein at codon 619 (p.Arg619Ter) was detected. This variant has not been reported in the 1000 genomes and has a MAF of 0.0008% in the gnomAD database. The in-silico predictions of the variant is damaging by MutationTaster2 and DANN. This variant has been previously reported in patient with MPS I (PMID: 31194252). In summary the variant meets our criteria to be classified as pathogenic.

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		0.38
Vest4		0.81
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121965031; hg19: chr4-998074;