4-1004292-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance 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): PM2 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/CA2802458/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:9

Conservation

PhyloP100: 1.51

Publications

23 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, 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

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

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 link	c.1861C>G	p.Arg621Gly	missense_variant	Exon 14 of 14	ENST00000514224.2	NP_000194.2	P35475-1
IDUA	NM_001363576.1 link	c.1465C>G	p.Arg489Gly	missense_variant	Exon 13 of 13		NP_001350505.1
IDUA	NR_110313.1 link	n.1953C>G		non_coding_transcript_exon_variant	Exon 14 of 14
IDUA	XM_047415650.1 link	c.*300C>G		downstream_gene_variant			XP_047271606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1861C>G	p.Arg621Gly	missense_variant	Exon 14 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1861C>G	p.Arg621Gly	missense_variant	Exon 14 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.1972C>G		non_coding_transcript_exon_variant	Exon 11 of 11	5
IDUA	ENST00000652070.1 link	n.1917C>G		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000278

AC:

AN:

248290

AF XY:

0.000274

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:

0.000198

Gnomad NFE exome

AF:

0.000552

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000206

AC:

301

AN:

1458874

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

725874

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000158

AC:

AN:

50488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000251

AC:

279

AN:

1111968

Other (OTH)

AF:

0.000199

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41348

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Uncertain:4

Dec 06, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance 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): PM2 Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 621 of the IDUA protein (p.Arg621Gly). This variant is present in population databases (rs121965025, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 444626). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:4

Jun 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Listed in one table of a publication as being seen heterozygous with unknown phase with a pathogenic variant in a patient with severe MPS I, but is unclear if this may represent a typographical error as this variant is not listed in the other two tables summarizing the identified variants but a nonsense variant at the same nucleotide position is listed (Voskoboeva et al., 2021); Has not otherwise been published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35141277, 34833038, 33301762, 27896125) -

Sep 20, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

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

Uncertain:1

Jan 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.013

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

1.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.73

Sift

Benign

0.042

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.93

P;.

Vest4

0.84

MVP

0.90

MPC

0.70

ClinPred

0.33

GERP RS

4.7

Varity_R

0.67

gMVP

0.95

Mutation Taster

=62/38

polymorphism

(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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4-1004292-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over