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rs772416503

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_SupportingPP4_ModeratePM2_SupportingPP3PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1487C>G variant in IDUA is a missense variant predicted to cause substitution of Proline by Arginine at amino acid 496 p.(Pro496Arg). At least 8 patients are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic or likely pathogenic by the ClinGen LD VCEP including c.793G>C (p.Gly265Arg) (ClinVar Variation ID: 638074) (PMID:21394825, LP, 0.25), c.152G>A (p.Gly51Asp) (ClinVar Variation ID: 193061) (PMID:21394825, P, 2 x 0.5), c.208C>T (p.Gln70Ter) (ClinVar Variation ID: 11909) (PMID:21394825, P, 4 patients, max 2 x 0.5), and c.1598C>G (p.Pro533Arg) (PMID:34408967, P, 0.5 points). One individual is homozygous for the variant (PMID:34408967, 0.5 points). This variant has also been reported in compound heterozygosity with p.Arg89Trp (PMID:21394825), c.1727+1G>A (PMID:21394825), c.1854C>A (p.Tyr618Ter) (PMID:27520059) and c.878_889dup (PMID 28752568). The allelic data from these patients will be used in the subsequent classification of then second variant and is not included here to avoid circular logic. Total 3.25 points (PM3_Strong). In one report (PMID:27520059), there was evidence of decreased IDUA enzyme activity, increased urine glycosaminoglycans and a specific clinical phenotype, allowing for application of PP4_Moderate. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000003515 (4/1137936 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). and has some experimental evidence suggesting absence of IDUA activity when the variant is expressed in Cos-7 cells (PMID:11735025) (PS3_Supporting). Computational predictor tools (REVEL score 0.72) suggest that this variant may be deleterious to IDUA function (PP3). A different missense variant, c.1487C>G (p.Pro496Leu) [ClinVar Variation ID 551675] in the same codon has been classified as likely pathogenic for MPS I by the ClinGen VCEP, however PM5 was not assigned to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 496861). 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: PM3_Strong, PP4_Moderate. PS3_Supporting, PM2_Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 5, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802275/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

12
7

Clinical Significance

Likely pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 2.63

Publications

10 publications found
Variant links:
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, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • Hurler syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
  • Hurler-Scheie syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000203.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
IDUA
NM_000203.5
MANE Select
c.1487C>Gp.Pro496Arg
missense
Exon 10 of 14NP_000194.2P35475-1
IDUA
NM_001363576.1
c.1091C>Gp.Pro364Arg
missense
Exon 9 of 13NP_001350505.1
IDUA
NR_110313.1
n.1575C>G
non_coding_transcript_exon
Exon 10 of 14

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
IDUA
ENST00000514224.2
TSL:2 MANE Select
c.1487C>Gp.Pro496Arg
missense
Exon 10 of 14ENSP00000425081.2P35475-1
IDUA
ENST00000247933.9
TSL:1
c.1487C>Gp.Pro496Arg
missense
Exon 10 of 14ENSP00000247933.4P35475-1
IDUA
ENST00000962389.1
c.1562C>Gp.Pro521Arg
missense
Exon 11 of 15ENSP00000632448.1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151960
Hom.:
0
Cov.:
33
show subpopulations
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:
0.0000139
AC:
2
AN:
143870
AF XY:
0.0000241
show subpopulations
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:
0.0000299
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000221
AC:
3
AN:
1359134
Hom.:
0
Cov.:
37
AF XY:
0.00000148
AC XY:
1
AN XY:
674164
show subpopulations
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:
0.00
AC:
0
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:
0.00000280
AC:
3
AN:
1069986
Other (OTH)
AF:
0.00
AC:
0
AN:
56088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151960
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74216
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

ClinVar submissions
Significance:Likely pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
6
-
-
Mucopolysaccharidosis type 1 (6)
2
-
-
not provided (2)
1
-
-
Hurler syndrome (1)
1
-
-
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Uncertain
2.7
M
PhyloP100
2.6
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-7.6
D
REVEL
Pathogenic
0.72
Sift
Uncertain
0.0020
D
Sift4G
Pathogenic
0.0
D
Varity_R
0.93
gMVP
0.94
Mutation Taster
=3/97
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

Other links and lift over

dbSNP: rs772416503;
hg19: chr4-996908;
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