dbSNP rs121965027: IDUA:p.Leu490Pro (chr4-1003102-T-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM1PP3_StrongPP5_Very_Strong

The NM_000203.5(IDUA):c.1469T>C(p.Leu490Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,512,716 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002521779: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23786846)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L490L) has been classified as Likely benign. The gene IDUA is included in the ClinGen Criteria Specification Registry.

Frequency

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

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.942

Publications

21 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

IDUA links:

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

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 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002521779: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23786846).; SCV001803931: Published functional studies demonstrate this variant results in reduced IDUA activity (Tieu et al., 1995); PMID: 28752568, 27146977, 21394825, 31400021, 31473686, 31589614, 23786846, 7550232; SCV001375542: Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232).; SCV001422525: "In vitro functional studies provide some evidence that the p.Leu490Pro variant may impact protein function (PMID: 7550232)."; SCV004037861: The most pronounced variant effect results in <10% of normal activity (example: Oussorena_2013). PMID: 23786846; SCV005440530: In vitro functional studies by Tieu et al indicate that this variant showed absence of enzyme activity.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000203.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 4-1003102-T-C is Pathogenic according to our data. Variant chr4-1003102-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 11919.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.1469T>C	p.Leu490Pro	missense	Exon 10 of 14	NP_000194.2	P35475-1
IDUA	NM_001363576.1		c.1073T>C	p.Leu358Pro	missense	Exon 9 of 13	NP_001350505.1
IDUA	NR_110313.1		n.1557T>C		non_coding_transcript_exon	Exon 10 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1469T>C	p.Leu490Pro	missense	Exon 10 of 14	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9	TSL:1	c.1469T>C	p.Leu490Pro	missense	Exon 10 of 14	ENSP00000247933.4	P35475-1
IDUA	ENST00000962389.1		c.1544T>C	p.Leu515Pro	missense	Exon 11 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151002

Hom.:

Cov.:

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000468

AC:

AN:

149530

AF XY:

0.0000581

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:

0.0000144

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1361714

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

675832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28332

American (AMR)

AF:

0.00

AC:

AN:

34076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23820

East Asian (EAS)

AF:

0.00

AC:

AN:

31248

South Asian (SAS)

AF:

0.000393

AC:

AN:

76386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070986

Other (OTH)

AF:

0.00

AC:

AN:

56072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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:

0.00000662

AC:

AN:

151002

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73728

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41078

American (AMR)

AF:

0.00

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5072

South Asian (SAS)

AF:

0.000208

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67734

Other (OTH)

AF:

0.00

AC:

AN:

2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hurler syndrome (5)

Mucopolysaccharidosis type 1 (5)

not provided (3)

Mucopolysaccharidosis, MPS-I-H/S (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Pathogenic

0.84

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.56

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.026

MutationAssessor

Benign

1.9

PhyloP100

0.94

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.56

Sift

Benign

0.19

Sift4G

Uncertain

0.041

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.86

Mutation Taster

=17/83

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

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over