4-1003120-C-T

Variant names:

• chr4-1003120-C-T
• rs772416503
• NM_000203.5:c.1487C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5_Supporting PS3_Supporting PM3 PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1487C>T variant in IDUA is a missense variant predicted to cause substitution of proline by leucine at amino acid 496, p.(Pro496Leu). This variant has been reported to account for 0.65% of disease-causing alleles in individuals with MPS I (PMIDs: 28752568, 7550232, 18463126). At least two probands have been reported to be compound heterozygous, phase not confirmed, for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (PMID:18463126, 28752568). Another patient has been reported who is compound heterozygous for the variant and c.223G>A (p.Ala75Thr) (PMID:7550232). The allelic data for this patient will be used in the classification of p.Ala75Thr and is not included here to avoid circular logic (PM3 applied; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000012 (1/80558 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When the variant was expressed in Cos-1 cells, IDUA activity was absent (PMID:7550232) (PS3_Supporting). Computational predictor tools (REVEL score 0.647) suggest that this variant may be deleterious to IDUA function (PP3). In addition, a different missense variant, c.1487C>G (p.Pro496Arg) [ClinVar Variation ID 496861] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 551675). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PS3_Supporting, PM2_Supporting, PM3, PM5_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA91170412/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:1
• Conservation: PhyloP100: 2.63
• Publications: 10 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: Likely_pathogenic. The variant received 6 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1487C>T	p.Pro496Leu	missense_variant	Exon 10 of 14	ENST00000514224.2	NP_000194.2
IDUA	NM_001363576.1	c.1091C>T	p.Pro364Leu	missense_variant	Exon 9 of 13		NP_001350505.1
IDUA	XM_047415650.1	c.1487C>T	p.Pro496Leu	missense_variant	Exon 10 of 12		XP_047271606.1
IDUA	NR_110313.1	n.1575C>T		non_coding_transcript_exon_variant	Exon 10 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1487C>T	p.Pro496Leu	missense_variant	Exon 10 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151960 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

GnomAD4 exome AF: 0.00000883 AC: 12 AN: 1359134 Hom.: 0 Cov.: 37 AF XY: 0.0000119 AC XY: 8 AN XY: 674164

African (AFR) AF: 0.00 AC: 0 AN: 28350

American (AMR) AF: 0.00 AC: 0 AN: 33442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23802

East Asian (EAS) AF: 0.00 AC: 0 AN: 31192

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5362

European-Non Finnish (NFE) AF: 0.0000103 AC: 11 AN: 1069986

Other (OTH) AF: 0.00 AC: 0 AN: 56088

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

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

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 496 of the IDUA protein (p.Pro496Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 7550232, 11735025). ClinVar contains an entry for this variant (Variation ID: 551675). 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) indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). This variant disrupts the p.Pro496 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11735025, 21394825, 27520059). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 06, 2024

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.1487C>T variant in IDUA is a missense variant predicted to cause substitution of proline by leucine at amino acid 496, p.(Pro496Leu). This variant has been reported to account for 0.65% of disease-causing alleles in individuals with MPS I (PMIDs: 28752568, 7550232, 18463126). At least two probands have been reported to be compound heterozygous, phase not confirmed, for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen LD VCEP, c.1205G>A (p.Trp402Ter) (PMID:18463126, 28752568). Another patient has been reported who is compound heterozygous for the variant and c.223G>A (p.Ala75Thr) (PMID: 7550232). The allelic data for this patient will be used in the classification of p.Ala75Thr and is not included here to avoid circular logic (PM3 applied; insufficient evidence to apply PP4). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000012 (1/80558 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). When the variant was expressed in Cos-1 cells, IDUA activity was absent (PMID: 7550232) (PS3_Supporting). Computational predictor tools (REVEL score 0.647) suggest that this variant may be deleterious to IDUA function (PP3). In addition, a different missense variant, c.1487C>G (p.Pro496Arg) [ClinVar Variation ID 496861] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen LD VCEP (PM5_Supporting). There is a ClinVar entry for this variant (Variation ID: 551675). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0.0): PS3_Supporting, PM2_Supporting, PM3, PM5_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) -

not provided Pathogenic:1 Uncertain:1

Dec 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7550232) -

Hurler syndrome Pathogenic:1

May 01, 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	0.65
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.7	M;.
PhyloP100		2.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.85
MVP		0.98
MPC		0.73
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.86
gMVP		0.93
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772416503; hg19: chr4-996908;