chr4-1002275-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000203.5(IDUA):c.979G>C(p.Ala327Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,950 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 (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 0.419

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 4-1002275-G-C is Pathogenic according to our data. Variant chr4-1002275-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 167190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1002275-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5 link	c.979G>C	p.Ala327Pro	missense_variant	Exon 8 of 14	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 link	c.979G>C	p.Ala327Pro	missense_variant	Exon 8 of 14	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000660

AC:

AN:

242572

Hom.:

AF XY:

0.0000606

AC XY:

AN XY:

131990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000586

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:

0.000120

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000143

AC:

209

AN:

1458728

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

725556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000180

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:6Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common pathogenic variant in Europe -

Jan 01, 2019

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in GnomAD -

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The IDUA c.979G>C (p.A327P) variant was reported in the compound heterozygous state in at least 4 patients with MPS I (PMID: 7550242; 112203999; 15300847; 19396826; 24368159). -

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 327 of the IDUA protein (p.Ala327Pro). This variant is present in population databases (rs199801029, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 7550242, 15300847, 19396826, 23786846, 24368159). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1067G>C. ClinVar contains an entry for this variant (Variation ID: 167190). Invitae Evidence 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 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: 15300847, 23786846). For these reasons, this variant has been classified as Pathogenic. -

Aug 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The IDUA c.979G>C (p.Ala327Pro) variant involves the alteration of a non-conserved nucleotide located in the Glycoside hydrolase superfamily domain (IPR017853) (InterPro). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively). Functional studies found very low enzymatic residual activity in homozygote and compound heterozygote MPS I patients (Oussorena__2013, Yogalingam_2004). The variant of interest has been found in a large, broad control population, ExAC in 7/90286 control chromosomes at a frequency of 0.0000775, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). This variant was found in multiple patients with MPS I, including homozygotes and compound heterozygotes (in trans with pathogenic variants such as c.878-889dup12, c.1205G>A/p.W402X, c.1154C>G/p.P385R, and c.1148G>A/R383H), and determined to be associated with a severe phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Ala327Pro variant in IDUA has been reported in at least 23 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 23786846, 7550242, 19396826, 24368159) and has been identified in 0.012% (15/123926) of European (non-Finnish) chromosomes, 0.006% (2/34992) of Latino chromosomes, and 0.004% (1/24138) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199801029). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 167190) as pathogenic by Counsyl, EGL Genetic Diagnostics, Integrated Genetics, Invitae, and GeneReviews. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on their Alpha-L-iduronidase levels being <1% of normal consistent with disease (PMID: 23786846). The presence of this variant in 3 affected homozygotes and in combination with a reported pathogenic variant in at least 14 individuals with MPS increases the likelihood that the p.Ala327Pro variant is pathogenic (VariationID: 11908; PMID: 28752568, 23786846, 7550242, 19396826). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on multiple occurrences in combination with other pathogenic variants in individuals with MPS and the phenotype of patients with the variant being highly specific for disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PP4 (Richards 2015). -

not provided

Pathogenic:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 21, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 30809705, 27896125, 8680403, 21394825, 27392569, 27511503, 28684085, 28752568, 10607946, 23786846, 9427149, 7550242, 24368159, 7951228, 15300847) -

Jun 06, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IDUA: PM3:Very Strong, PM2, PS3:Supporting -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hurler syndrome

Pathogenic:2

Apr 29, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This IDUA variant has been previously reported in patients with mucopolysaccharidosis I in the presence of a second known disease-causing variant. Although the alanine residue at this position is not evolutionarily conserved across species assessed, funcational analysis in patient cells support that c.979G>C results in reduced IDUA ensymatic activity. This variant (rs199801029) is rare (<0.1%) in a large population dataset (gnomAD: 19/273938 total alleles; 0.006936%; no homozygotes). Six submitters in ClinVar6 classify this variant as either pathogenic or likely pathogenic. We consider it to be pathogenic. -

May 22, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

May 24, 2024

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

0.90

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.76

D;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.90

D;.

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.22

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.34

B;.

Vest4

0.84

MVP

0.98

MPC

0.32

ClinPred

0.18

GERP RS

3.6

Varity_R

0.67

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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