Genetic Variant IDUA:p.Ser633Leu (chr4-1004329-C-T) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000203.5(IDUA):c.1898C>T(p.Ser633Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000869 in 1,611,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001577977: Experimental studies have shown that this missense change affects IDUA function (PMID:11735025)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S633W) has been classified as Likely pathogenic. The gene IDUA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.17

Publications

17 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: 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

IDUA links:

Genome browser will be placed here

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001577977: Experimental studies have shown that this missense change affects IDUA function (PMID: 11735025).; SCV005439044: Experimental studies have shown that this missense change affects IDUA function Beesley CE, et al., 2001.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000203.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-1004329-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 286242.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 4-1004329-C-T is Pathogenic according to our data. Variant chr4-1004329-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 556406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDUA	NM_000203.5	MANE Select	c.1898C>T	p.Ser633Leu	missense	Exon 14 of 14	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.1502C>T	p.Ser501Leu	missense	Exon 13 of 13	NP_001350505.1
IDUA	NR_110313.1		n.1990C>T		non_coding_transcript_exon	Exon 14 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1898C>T	p.Ser633Leu	missense	Exon 14 of 14	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.1898C>T	p.Ser633Leu	missense	Exon 14 of 14	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.1973C>T	p.Ser658Leu	missense	Exon 15 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000120

AC:

AN:

249054

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459632

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000390

AC:

AN:

51306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis type 1 (2)

Mucopolysaccharidosis, MPS-I-H/S (2)

Hurler syndrome (1)

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.8

PhyloP100

4.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.71

MVP

0.97

MPC

0.71

ClinPred

0.98

GERP RS

5.5

Varity_R

0.85

gMVP

0.97

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over