rs121965029

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-987916-G-A
• chr4-987916-G-C

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: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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.

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.266G>A	p.Arg89Gln	missense	Exon 2 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_022042.4	MANE Select	c.*917C>T		3_prime_UTR	Exon 3 of 3	NP_071325.2
	SLC26A1	NM_213613.4		c.*917C>T		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.266G>A	p.Arg89Gln	missense	Exon 2 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.266G>A	p.Arg89Gln	missense	Exon 2 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*917C>T		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Mucopolysaccharidosis type 1 (6)
1	-	-	Hurler syndrome (1)
1	-	-	Mucopolysaccharidosis, MPS-I-H/S (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;