rs148789453

Variant names:

• chr4-1001802-T-A
• rs148789453
• NM_000203.5:c.713T>A

Your query was ambiguous. Multiple possible variants found:

• chr4-1001802-T-A
• chr4-1001802-T-C
• chr4-1001802-T-G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4_Moderate PM2_Supporting PM3 PP3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000203.5: c.713T>A variant in IDUA is a missense variant predicted to cause substitution of Leu by Gln at amino acid 238 (p.Leu238Gln). This variant has been detected in at least 18 individuals with MPS I, the majority of whom had phenotypes consistent with a clinical diagnosis of Hurler-Scheie (PMID:32188113, 31839529, 34984346, 26260077, 28125077, and others). All of those individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases; it is unknown if these variants were confirmed in trans. For example, in compound heterozygous patients, the second variant is p.Gln70Ter (1 patient, 0.5 points, PMID:31194252), p.Trp402Ter (2 patients, 2 x 0.5 points, PMID:31194252), c.386-2A>G (1 patient 0.5 points, PMID:31194252), p.Glu182Lys (1 patient, 0.5 points, PMID:31194252), Int3-2a>g (1 patient, 0.5 points, PMID:31839529) and 63del (one patient, 0.5 points, PMID:31839529)Total 4 points (PM3_VeryStrong). One of these individuals was an adult male with clinical features consistent with MPS I including coarse facial features, joint stiffness, heart murmur, mitral and aortic stenosis, retinal degeneration and optic disc edema, and ventriculomegaly, elevated urine keratan sulfate and dermatan sulfate, undetectable serum IDUA activity (PMID:34984346) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004 (3/74,858 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another missense variant c.713T>C p.Leu238Pro in the same codon has been reported in the ClinVar database in association with MPS I (ClinVar Variation ID 1517837). However, this variant has not yet been evaluated by the ClinGen Lysosomal Diseases VCEP (PM5 not met). Expression of the variant in CHO cells showed 5.88% wild type IDUA activity (PMID:15300847). However, this result does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP to apply PS3_Supporting criterion because the activity level was above the threshold of <2% established for this assay. The computational predictor REVEL gives a score of 0.904, 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: 265418). In summary, this variant meets the criteria to be classified as 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_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802065/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 6.04
• Publications: 14 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 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.
• 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.713T>A	p.Leu238Gln	missense_variant	Exon 6 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.317T>A	p.Leu106Gln	missense_variant	Exon 5 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.713T>A	p.Leu238Gln	missense_variant	Exon 6 of 12		XP_047271606.1
IDUA	NR_110313.1	n.801T>A		non_coding_transcript_exon_variant	Exon 6 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.713T>A	p.Leu238Gln	missense_variant	Exon 6 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

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: 0.0000218 AC: 5 AN: 229094 AF XY: 0.0000239

Gnomad AFR exome AF: 0.000144

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: 0.0000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452456 Hom.: 0 Cov.: 34 AF XY: 0.00000554 AC XY: 4 AN XY: 722324

African (AFR) AF: 0.0000299 AC: 1 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 43840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39408

South Asian (SAS) AF: 0.00 AC: 0 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109692

Other (OTH) AF: 0.00 AC: 0 AN: 60042

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152184 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

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

Alfa AF: 0.0000207 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Jan 30, 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 glutamine, which is neutral and polar, at codon 238 of the IDUA protein (p.Leu238Gln). This variant is present in population databases (rs148789453, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847, 24368159; Invitae). ClinVar contains an entry for this variant (Variation ID: 265418). 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 with a positive predictive value of 95%. This variant disrupts the p.Leu238 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been observed in individuals with IDUA-related conditions (PMID: 21480867, 24368159), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Dec 06, 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.713T>A variant in IDUA is a missense variant predicted to cause substitution of Leu by Gln at amino acid 238 (p.Leu238Gln). This variant has been detected in at least 18 individuals with MPS I, the majority of whom had phenotypes consistent with a clinical diagnosis of Hurler-Scheie (PMID: 32188113, 31839529, 34984346, 26260077, 28125077, and others). All of those individuals were compound heterozygous for the variant and another variant that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases; it is unknown if these variants were confirmed in trans. For example, in compound heterozygous patients, the second variant is p.Gln70Ter (1 patient, 0.5 points, PMID: 31194252), p.Trp402Ter (2 patients, 2 x 0.5 points, PMID: 31194252), c.386-2A>G (1 patient 0.5 points, PMID: 31194252), p.Glu182Lys (1 patient, 0.5 points, PMID: 31194252), Int3-2a>g (1 patient, 0.5 points, PMID: 31839529) and 63del (one patient, 0.5 points, PMID: 31839529) Total 4 points (PM3_VeryStrong). One of these individuals was an adult male with clinical features consistent with MPS I including coarse facial features, joint stiffness, heart murmur, mitral and aortic stenosis, retinal degeneration and optic disc edema, and ventriculomegaly, elevated urine keratan sulfate and dermatan sulfate, undetectable serum IDUA activity (PMID: 34984346) (PP4_Moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004 (3/74,858 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Another missense variant c.713T>C p.Leu238Pro in the same codon has been reported in the ClinVar database in association with MPS I (ClinVar Variation ID 1517837). However, this variant has not yet been evaluated by the ClinGen Lysosomal Diseases VCEP (PM5 not met). Expression of the variant in CHO cells showed 5.88% wild type IDUA activity (PMID: 15300847). However, this result does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP to apply PS3_Supporting criterion because the activity level was above the threshold of <2% established for this assay. The computational predictor REVEL gives a score of 0.904, 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: 265418). In summary, this variant meets the criteria to be classified as 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_Very Strong, PP3_Moderate, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

Jan 14, 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.Leu238Gln variant in IDUA has been reported in at least 7 individuals with mucopolysaccharidosis (MPS), segregated with disease in 4 affected relatives from 2 families (PMID: 24368159), and has been Identified in 0.014% (2/13914) of African chromosomes and 0.003% (3/102956) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148789453). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Leu238Gln variant may impact protein function (PMID: 15300847). However, these types of assays may not accurately represent biological function. 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 presence of this variant in combination with reported pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Leu238Gln variant is pathogenic (VariationID: 11908, 222994; PMID: 24368159). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1%, consistent with disease (PMID: 15300847). 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 known pathogenic variants, functional studies, cosegregation, and the phenotype of individuals with the variant and MPS being highly specific for IDUA. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PM2_supporting, PP3, PP4, PP1 (Richards 2015). -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 07, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the L238Q variant causes reduced IDUA activity and protein levels when expressed in Chinese hamster ovary (CHO) cells (Yogalingam et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15300847, 24368159, 26260077, 31194252) -

IDUA-related disorder Pathogenic:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IDUA c.713T>A variant is predicted to result in the amino acid substitution p.Leu238Gln. This variant was reported along with second variant in several individuals with Mucopolysaccharidosis type 1 (Yogalingam et al. 2004. PubMed ID: 15300847; Ahmed et al. 2013. PubMed ID: 24368159). In vitro functional study demonstrated that this variant reduces IDUA activity to 5.88% of normal enzyme activity (Table 3, Yogalingam et al. 2004. PubMed ID: 15300847). Alternative variant at the same codon p.Leu238Arg has been observed in an individual with Mucopolysaccharidosis type 1 (Wang et al. 2011. PubMed ID: 21480867). This variant is reported in 0.014% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Hurler syndrome Pathogenic:1

Aug 10, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.;D;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T;.;.;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.91
MVP		1.0
MPC		0.77
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.98
Mutation Taster		=2/98	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: rs148789453; hg19: chr4-995590;