4-1004329-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_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 (★★).

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:6

Conservation

PhyloP100: 4.17

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 556406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.1898C>T	p.Ser633Leu	missense_variant	Exon 14 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IDUA	ENST00000514224.2 link	c.1898C>T	p.Ser633Leu	missense_variant	Exon 14 of 14	2	NM_000203.5	ENSP00000425081.2	P35475-1
IDUA	ENST00000247933.9 link	c.1898C>T	p.Ser633Leu	missense_variant	Exon 14 of 14	1		ENSP00000247933.4	P35475-1
IDUA	ENST00000514698.5 link	n.2009C>T		non_coding_transcript_exon_variant	Exon 11 of 11	5
IDUA	ENST00000652070.1 link	n.1954C>T		non_coding_transcript_exon_variant	Exon 13 of 13

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249054

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135252

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000390

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:2

Apr 09, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 633 of the IDUA protein (p.Ser633Leu). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). ClinVar contains an entry for this variant (Variation ID: 556406). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 11735025). For these reasons, this variant has been classified as Pathogenic. -

Hurler syndrome

Pathogenic:2

Jan 30, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.84 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000556406 /PMID: 11735025) and a different missense change at the same codon (p.Ser633Trp / ClinVar ID: VCV000286242 /PMID: 24798265) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.1898C>Tp.Ser633Leu variant in IDUA gene has been reported previously in multiple individuals affected with mucopolysaccharidosis Uttarilli A, et al., 2016; Kunin-Batson AS, et al., 2016; Wang X, et al., 2012; Beesley CE, et al., 2001. Experimental studies have shown that this missense change affects IDUA function Beesley CE, et al., 2001. The p.Ser633Leu variant has been reported with allele frequency of 0.001% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic multiple submissions. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on IDUA gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 633 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as pathogenic. In absence of another reportable variant in IDUA gene, the molecular diagnosis is not confirmed. -

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

Pathogenic:1

Mar 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;.

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.71

MVP

0.97

MPC

0.71

ClinPred

0.98

GERP RS

5.5

Varity_R

0.85

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over