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: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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.

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.713T>A	p.Leu238Gln	missense	Exon 6 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.317T>A	p.Leu106Gln	missense	Exon 5 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.801T>A		non_coding_transcript_exon	Exon 6 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.713T>A	p.Leu238Gln	missense	Exon 6 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.713T>A	p.Leu238Gln	missense	Exon 6 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.788T>A	p.Leu263Gln	missense	Exon 7 of 15	ENSP00000632448.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Mucopolysaccharidosis type 1 (4)
2	-	-	not provided (2)
1	-	-	Hurler syndrome (1)
1	-	-	IDUA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	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;