chr4-987916-G-A

Variant names:

• chr4-987916-G-A
• rs121965029
• NM_000203.5:c.266G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2_Supporting PP4 PM3_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.266G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 89 (p.Arg89Gln). This variant accounts for up to 24% of alleles in Japanese individuals with MPS I (PMID:8664897). At least 8 probands have been reported with the variant, typically with milder clinical features of MPS I and reduced IDUA activity (PMID:8213840, 8664897, 2148086) (PP4). Of those individuals, 4 probands and one sibling, were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. None of those were confirmed in trans. The second variants is c.1205G>A (p.Trp402Ter) (PMID:8213840, 2 patients, 2 x 0.5) and c.613_617dup (p.Glu207AlafsTer29) (PMID:8664897, 2 probands, 0.5 x 2). Four individuals are homozygous for the variant (PMIDs: 8664897, 21480867, max 2 x 0.5 points). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001662 (1/6016 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). This variant alters amino acid Arg89, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID:14559116;15862278) (PM1). The computational predictor REVEL gives a score of 0.941 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID:36413997) (PP3_Moderate). When expressed in CHO cells, the variant results in <5% WT activity (PMID:14559116), and reduced amount of protein, and reduced specific activity (PMID:14559116). Two other variants at the same amino acid position, c.265C>G (p.Arg89Gly) (ClinVar Variation ID: 2843836) and c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), have been reported. The evidence for pathogenicity for p.Arg89Gln will be used in the classification of the other two variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 11922). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 1.0.0): PM3_strong, PM1, PP4, PP3_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA256124/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.66
• Publications: 26 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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: 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.
• PP3: 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.266G>A	p.Arg89Gln	missense_variant	Exon 2 of 14	ENST00000514224.2	NP_000194.2
SLC26A1	NM_022042.4	c.*917C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000398516.3	NP_071325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.266G>A	p.Arg89Gln	missense_variant	Exon 2 of 14	2	NM_000203.5	ENSP00000425081.2
SLC26A1	ENST00000398516.3	c.*917C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_022042.4	ENSP00000381528.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000916 AC: 2 AN: 218452 AF XY: 0.00000841

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1448664 Hom.: 0 Cov.: 30 AF XY: 0.0000167 AC XY: 12 AN XY: 719582

African (AFR) AF: 0.00 AC: 0 AN: 33202

American (AMR) AF: 0.00 AC: 0 AN: 43076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39010

South Asian (SAS) AF: 0.00 AC: 0 AN: 84450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51070

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5700

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106408

Other (OTH) AF: 0.00 AC: 0 AN: 59886

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:6

Jun 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 89 of the IDUA protein (p.Arg89Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8680403, 21462124, 29282708). ClinVar contains an entry for this variant (Variation ID: 11922). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. 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. -

Mar 22, 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.266G>A (p.Arg89Gln) results in a conservative amino acid change located in the Glycoside hydrolase superfamily of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 62804 control chromosomes (ExAC). The variant, c.266G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A reputable database, GeneReviews classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

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.Arg89Gln variant in IDUA has been reported in at least 13 individuals with mucopolysaccharidosis (MPS), segregated with disease in 5 affected relatives from 2 families (PMID: 8213840, 8664897, 14559116, 28752568, 11735025, 21480867, and has been identified in 0.006% (1/16554) of East Asian chromosomes and 0.001% (1/94316) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965029). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has been reported pathogenic in ClinVar by Integrated Genetics, OMIM, and GeneReviews (VariationID: 26961). In vitro functional studies provide some evidence that the p.Arg89Gln variant may impact protein function based on reduced protein levels in cells transfected with the variant (PMID: 14559116). However, these types of assays may not accurately represent biological function. The presence of this variant in 4 affected homozygotes and in combination with at least 1 reported pathogenic variant and in 2 individuals with MPS increases the likelihood that the p.Arg89Gln variant is pathogenic (VariationID: 11908; PMID: 8213840, 8664897, 14559116, 28752568). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for MPS based on significantly reduced alpha-L-iduronidase activity levels consistent with disease (PMID: 14559116). The p.Arg89Gln is located in the active site of IDUA, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 14559116, 15862278). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences with pathogenic IDUA variants in individuals with MPS, in vitro functional studies, and low prevalence of the variant in the population. ACMG/AMP Criteria applied: PM3_strong, PM2, PM1, PS3_moderate, PP3, PM5_supporting, PP4, PP1 (Richards 2015). -

Apr 07, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.266G>A variant in IDUA is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 89 (p.Arg89Gln). This variant accounts for up to 24% of alleles in Japanese individuals with MPS I (PMID: 8664897). At least 8 probands have been reported with the variant, typically with milder clinical features of MPS I and reduced IDUA activity (PMID: 8213840, 8664897, 2148086) (PP4). Of those individuals, 4 probands and one sibling, were compound heterozygous for the variant and variant that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP. None of those were confirmed in trans. The second variants is c.1205G>A (p.Trp402Ter) (PMID: 8213840, 2 patients, 2 x 0.5) and c.613_617dup (p.Glu207AlafsTer29) (PMID: 8664897, 2 probands, 0.5 x 2). Four individuals are homozygous for the variant (PMIDs: 8664897, 21480867, max 2 x 0.5 points). Total 3 points (PM3_Strong). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001662 (1/6016 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). This variant alters amino acid Arg89, a residue that has been shown to be important in the active site pocket and substrate binding in IDUA, and therefore has been defined as a critical residue by the ClinGen Lysosomal Diseases VCEP (PMID: 14559116;15862278) (PM1). The computational predictor REVEL gives a score of 0.941 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). When expressed in CHO cells, the variant results in <5% WT activity (PMID: 14559116), and reduced amount of protein, and reduced specific activity (PMID: 14559116). Two other variants at the same amino acid position, c.265C>G (p.Arg89Gly) (ClinVar Variation ID: 2843836) and c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), have been reported. The evidence for pathogenicity for p.Arg89Gln will be used in the classification of the other two variants and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 11922). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Expert Panel (Specifications Version 1.0.0): PM3_strong, PM1, PP4, PP3_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on April 7, 2025). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 22, 2021

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Common pathogenic variant in Japan; causes attenuated MPS I. May change ability of α-L-iduronidase to affect catalysis. Deleterious effect appears to be potentiated by a polymorphism, p.Ala361Thr -

Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hurler syndrome Pathogenic:1

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.95		Loss of MoRF binding (P = 0.0317);
MVP		1.0
MPC		0.81
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.95
Mutation Taster		=13/87	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: rs121965029; hg19: chr4-981704; COSMIC: COSV99926580; COSMIC: COSV99926580;