rs758452450

Variant names:

• chr4-987873-G-A
• rs758452450
• NM_000203.5:c.223G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-987873-G-A
• chr4-987873-G-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3_Supporting PP4_Moderate PM2_Supporting PM3_Strong PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.223G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 75, p.(Ala75Thr). This variant has been seen in at least 11 unrelated patients. Six of these patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic, phase not confirmed: c.208C>T (p.Gln70Ter) (PMID:28752568, 35141277) (ClinVar Variation ID: 11909; 3 patients; max 2 patients counted, 2 x 0.5), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID:28752568, 8019563) (3 patients; max 2 patients counted, 2 x 0.5), and 2 individuals are homozygous for the variant (PMID:11735025, 27146977). In addition, three individuals are compound heterozygous for the variant and either c.895C>T (PMID:27146977), c.1898C>T (p.Ser633Leu) (PMID:16438163) or c.1650+1G>T (PMID:29843745). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Total points = 3 points (PM3_Strong). One of these individuals has specific clinical features (dysostosis multiplex, hepatosplenomegaly, corneal clouding and coarse facial features), with undetectable IDUA enzyme activity compared to Thai controls, and elevated urinary dermatan and heparan sulfate excretion (PMID:16438163). This is sufficient for use of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74900 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025). Expression of the variant in COS-1 cells resulted in no residual wild type IDUA activity (once background activity subtracted), indicating that this variant may impact protein function (PMID:7550232)(PS3_Supporting). The computational predictor REVEL gives a score of 0.803 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). There is a ClinVar entry for this variant (Variation ID: 222993). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0.): PM3_Strong, PP3_Moderate, PP4_Moderate. PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 4, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA356994/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.51
• Publications: 11 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.

• PS3: 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.223G>A	p.Ala75Thr	missense_variant	Exon 2 of 14	ENST00000514224.2	NP_000194.2
SLC26A1	NM_022042.4	c.*960C>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.223G>A	p.Ala75Thr	missense_variant	Exon 2 of 14	2	NM_000203.5	ENSP00000425081.2
SLC26A1	ENST00000398516.3	c.*960C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_022042.4	ENSP00000381528.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000827 AC: 2 AN: 241700 AF XY: 0.00000759

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: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1459778 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726154

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111698

Other (OTH) AF: 0.0000497 AC: 3 AN: 60336

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:5

May 04, 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.223G>A variant in IDUA is a missense variant predicted to cause substitution of alanine by threonine at amino acid 75, p.(Ala75Thr). This variant has been seen in at least 11 unrelated patients. Six of these patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic, phase not confirmed: c.208C>T (p.Gln70Ter) (PMID: 28752568, 35141277) (ClinVar Variation ID: 11909; 3 patients; max 2 patients counted, 2 x 0.5), c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (PMID: 28752568, 8019563) (3 patients; max 2 patients counted, 2 x 0.5), and 2 individuals are homozygous for the variant (PMID: 11735025, 27146977). In addition, three individuals are compound heterozygous for the variant and either c.895C>T (PMID: 27146977), c.1898C>T (p.Ser633Leu) (PMID: 16438163) or c.1650+1G>T (PMID: 29843745). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Total points = 3 points (PM3_Strong). One of these individuals has specific clinical features (dysostosis multiplex, hepatosplenomegaly, corneal clouding and coarse facial features), with undetectable IDUA enzyme activity compared to Thai controls, and elevated urinary dermatan and heparan sulfate excretion (PMID: 16438163). This is sufficient for use of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00001335 (1/74900 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025). Expression of the variant in COS-1 cells resulted in no residual wild type IDUA activity (once background activity subtracted), indicating that this variant may impact protein function (PMID: 7550232)(PS3_Supporting). The computational predictor REVEL gives a score of 0.803 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). There is a ClinVar entry for this variant (Variation ID: 222993). In summary, this variant meets the criteria to be classified as pathogenic. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications version 1.0.0.): PM3_Strong, PP3_Moderate, PP4_Moderate. PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 4, 2025) -

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 75 of the IDUA protein (p.Ala75Thr). 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, 11735025, 16438163, 27146977, 29843745). 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: 222993). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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.Ala75Thr variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 29843745, 27146977, 28752568) and has been identified in 0.002% (3/121916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758452450). 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 also been reported in ClinVar (VariationID: 222993) as pathogenic by Counsyl and GeneReviews. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase activity, consistent with disease (PMID: 27146977). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic and likely pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Ala75Thr variant is pathogenic (VariationID: 11908, 11909; PMID: 29843745, 27146977, 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic or likely pathogenic variants in individuals with MPS and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). -

Mar 31, 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.223G>A (p.Ala75Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase domain (IPR000514) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241700 control chromosomes. c.223G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (example, Clarke_1994, Ghosh_2017). 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 (example, Tieu_1995). Four clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

May 22, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hurler syndrome Pathogenic:1

Nov 16, 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
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.80
Sift	Benign	0.056	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.91		Loss of stability (P = 0.0056);
MVP		0.99
MPC		0.74
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.75
Mutation Taster		=48/52	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: rs758452450; hg19: chr4-981661;