rs794726878

Variant names:

• chr4-987137-T-C
• rs794726878
• NM_000203.5:c.53T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.53T>C variant in IDUA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 18 (p.Leu18Pro). This variant has been detected in at least 10 individuals with MPS I. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, three were homozygous for the variant (PMID 25256405, max 2 x 0.5 = 1 point). Four of the remaining individuals are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP including c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908) (PMID 31194252, at least one patient, phase not confirmed, 0.5 point), c.208C>T p.(Gln70Ter) (ClinVar Variation ID: 11909) (PMID 31194252, 255574391 2 patients, phase not confirmed, 2 x 0.5 point), and c.1487C>G p.(Pro496Arg) (PMID 31194252, 1 patient, phase not confirmed, 0.25 point). Two patients are compound heterozygous for the variant and c.1163C>A, p.(Thr388Lys), however the allelic data for these patients will be used to support the classification of Thr388Lys and is not included here in order to avoid circular logic (2.75 points, PM3_strong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of attenuated MPS1, presenting with reduced IDUA enzyme activity (0.73 nmol/h/mg, reference range 32-56) and increased GAG excretion in urine (188ug GAGs/g creatinine, age-related reference 67-124). His brother, also homozygous for the variant is reported to have attenuated MPS1, with similar clinical features (PMID 25256405) (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002779 (1/35,980 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.319 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. There is a ClinVar entry for this variant (Variation ID: 193062). In summary, this variant meets the criteria to be classified as likely 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_strong, PP4_moderate, PM2_supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 19, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA238566/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 36)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 0.633
• Publications: 5 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]

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• 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.53T>C	p.Leu18Pro	missense_variant	Exon 1 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.53T>C	p.Leu18Pro	missense_variant	Exon 1 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00 AC: 0 AN: 52646 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000236 AC: 3 AN: 1271464 Hom.: 0 Cov.: 36 AF XY: 0.00000480 AC XY: 3 AN XY: 625068

African (AFR) AF: 0.00 AC: 0 AN: 25150

American (AMR) AF: 0.00 AC: 0 AN: 20716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20510

East Asian (EAS) AF: 0.00 AC: 0 AN: 27400

South Asian (SAS) AF: 0.00 AC: 0 AN: 63772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3650

European-Non Finnish (NFE) AF: 0.00000292 AC: 3 AN: 1026342

Other (OTH) AF: 0.00 AC: 0 AN: 52364

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151980 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 18 of the IDUA protein (p.Leu18Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 25256405, 25557439, 31194252). ClinVar contains an entry for this variant (Variation ID: 193062). 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. For these reasons, this variant has been classified as Pathogenic. -

May 19, 2025

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000203.5:c.53T>C variant in IDUA is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 18 (p.Leu18Pro). This variant has been detected in at least 10 individuals with MPS I. This variant has been detected in at least 10 individuals with MPS I. Of those individuals, three were homozygous for the variant (PMID 25256405, max 2 x 0.5 = 1 point). Four of the remaining individuals are compound heterozygous for this variant and a second variant that has been classified as pathogenic or likely pathogenic for MPS I by the ClinGen Lysosomal Diseases VCEP including c.1205G>A p.(Trp402Ter) (ClinVar Variation ID: 11908) (PMID 31194252, at least one patient, phase not confirmed, 0.5 point), c.208C>T p.(Gln70Ter) (ClinVar Variation ID: 11909) (PMID 31194252, 255574391 2 patients, phase not confirmed, 2 x 0.5 point), and c.1487C>G p.(Pro496Arg) (PMID 31194252, 1 patient, phase not confirmed, 0.25 point). Two patients are compound heterozygous for the variant and c.1163C>A, p.(Thr388Lys), however the allelic data for these patients will be used to support the classification of Thr388Lys and is not included here in order to avoid circular logic (2.75 points, PM3_strong). One patient with this variant present in the homozygous state has been reported with a clinical diagnosis of attenuated MPS1, presenting with reduced IDUA enzyme activity (0.73 nmol/h/mg, reference range 32-56) and increased GAG excretion in urine (188ug GAGs/g creatinine, age-related reference 67-124). His brother, also homozygous for the variant is reported to have attenuated MPS1, with similar clinical features (PMID 25256405) (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002779 (1/35,980 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.319 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on IDUA function. There is a ClinVar entry for this variant (Variation ID: 193062). In summary, this variant meets the criteria to be classified as likely 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_strong, PP4_moderate, PM2_supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 19, 2025). -

Jan 13, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MSP increases the likelihood that the p.Leu18Pro variant is pathogenic (VariationID: 11909, 11908; PMID: 25256405, 25557439). The phenotype of individuals homozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 25256405). The p.Leu18Pro variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 25256405). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM1, PM2_supporting, PP4 (Richards 2015). -

Hurler syndrome Pathogenic:3

Mar 11, 2023

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000193062 /PMID: 25256405). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31194252, 25256405). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 22, 2018

Counsyl

Significance: Likely 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. -

not provided Pathogenic:2 Uncertain:1

Apr 13, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25256405, 25557439) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.48
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.34	T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.4	L;.
PhyloP100		0.63
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.0	B;.
Vest4		0.38
MutPred		0.37		Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);
MVP		0.62
MPC		0.30
ClinPred		0.54	D
GERP RS		-1.4
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.74
Mutation Taster		=20/80	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: rs794726878; hg19: chr4-980925;