rs776787370

Variant names:

• chr4-1004027-C-G
• rs776787370
• NM_000203.5:c.1743C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-1004027-C-G
• chr4-1004027-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.1743C>G (p.Tyr581Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13 out of 14. While the premature stop codon is predicted to occur in the penultimate exon of the gene, it is 5' to the last 50 nucleotides of the exon and, therefore, this variant is expected to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 5 patients with this variant and a diagnosis of MPS I, confirmed by reduced IDUA activity, have been reported. This included patients with documented laboratory values indicating undetectable IDUA activity along with clinical features such as intellectual disability, dysmorphic facial features, multiple dysostosis, joint stiffness, hepatosplenomegaly, umbilical hernia, chronic rhinorrhea, and hydrocephalus (PMID:22074387, 27196898) (PP4). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908, PMID:3351789); the phase is unknown (0.5 points). Two Tunisian patients are homozygous for the variant (PMID:22074387) (2 x 0.5 points). A further two patients are compound heterozygous for the variant and p.Pro533Arg (PMID:12796790, 27196898); the allelic data from these patients will be used in the classification of p.Pro533Arg and are not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00008921 (4/44840 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1, PM3, PP4, 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/CA2802392/MONDO:0001586/091

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: -1.53
• Publications: 12 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1743C>G	p.Tyr581*	stop_gained	Exon 13 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1347C>G	p.Tyr449*	stop_gained	Exon 12 of 13		NP_001350505.1
IDUA	NR_110313.1	n.1835C>G		non_coding_transcript_exon_variant	Exon 13 of 14
IDUA	XM_047415650.1	c.*35C>G		3_prime_UTR_variant	Exon 12 of 12		XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1743C>G	p.Tyr581*	stop_gained	Exon 13 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1743C>G	p.Tyr581*	stop_gained	Exon 13 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1854C>G		non_coding_transcript_exon_variant	Exon 10 of 11	5
IDUA	ENST00000652070.1	n.1799C>G		non_coding_transcript_exon_variant	Exon 12 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251162 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461088 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726848

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111784

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Nov 11, 2021

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.1743C>G (p.Tyr581X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251162 control chromosomes (gnomAD). c.1743C>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (e.g. Souillet_2003, Chkioua_2011, Tebani_2016, Guffon_2021). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 08, 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.Tyr581*) 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 (rs776787370, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21394825, 27196898). ClinVar contains an entry for this variant (Variation ID: 550883). For these reasons, this variant has been classified as Pathogenic. -

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:c.1743C>G (p.Tyr581Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13 out of 14. While the premature stop codon is predicted to occur in the penultimate exon of the gene, it is 5' to the last 50 nucleotides of the exon and, therefore, this variant is expected to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least 5 patients with this variant and a diagnosis of MPS I, confirmed by reduced IDUA activity, have been reported. This included patients with documented laboratory values indicating undetectable IDUA activity along with clinical features such as intellectual disability, dysmorphic facial features, multiple dysostosis, joint stiffness, hepatosplenomegaly, umbilical hernia, chronic rhinorrhea, and hydrocephalus (PMID: 22074387, 27196898) (PP4). One patient is compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908, PMID: 3351789); the phase is unknown (0.5 points). Two Tunisian patients are homozygous for the variant (PMID: 22074387) (2 x 0.5 points). A further two patients are compound heterozygous for the variant and p.Pro533Arg (PMID: 12796790, 27196898); the allelic data from these patients will be used in the classification of p.Pro533Arg and are not included here to avoid circular logic. Total 1.5 points (PM3). The highest population minor allele frequency in gnomAD v4.1.0. is 0.00008921 (4/44840 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.0025), meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0.): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) -

not provided Pathogenic:2

Jun 07, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2021

GeneDx

Significance: Likely 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 73 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21394825, 27196898, 9672523, 21521498, 21639919, 32432561, 33072983, 33147872, 30442156, 25525159) -

Hurler syndrome Pathogenic:1

Feb 27, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.018	N
PhyloP100		-1.5
Vest4		0.61
GERP RS		-5.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776787370; hg19: chr4-997815;