rs781136336

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000203.5(IDUA):c.1577T>C(p.Leu526Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,522,386 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 1.82

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 4-1003397-T-C is Pathogenic according to our data. Variant chr4-1003397-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567566.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=1}. Variant chr4-1003397-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.1577T>C	p.Leu526Pro	missense_variant	11/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.1577T>C	p.Leu526Pro	missense_variant	11/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

151922

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000336

AC:

AN:

118962

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

65432

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 SAS exome

AF:

0.000708

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000566

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000404

AC:

554

AN:

1370464

Hom.:

Cov.:

AF XY:

0.000413

AC XY:

279

AN XY:

676024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000575

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000526

Gnomad4 FIN exome

AF:

0.0000299

Gnomad4 NFE exome

AF:

0.000460

Gnomad4 OTH exome

AF:

0.000280

GnomAD4 genome

AF:

0.000270

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000728

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.000179

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2024	Variant summary: IDUA c.1577T>C (p.Leu526Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 118962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00034 vs 0.0027), allowing no conclusion about variant significance. c.1577T>C has been reported in the literature in newborn screening studies (e.g. Donati_2018, Wasserstein_2019, Polo_2020, Bosfield_2021). One newborn in particular was found to be homozygous for this variant and exhibited urinary and dried blood spot glycosaminoglycan (GAG) levels within normal range (Donati_2018, Polo_2020). However, no follow-up data from a later stage of life were available to determine the actual phenotype. In contrast, a second homozygous individual was reported who had a clinical diagnosis of Mucopolysaccharidosis Type 1 with an attenuated phenotype (Zhang_2022). Importantly, the variant was also detected in combination with other known pathogenic variants in individuals affected with Mucopolysaccharidosis Type 1 (Pollard_2013, Dickson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33098355, 31194252, 26260077, 30442156, 22976768, 32432561, 30093709, 35787971). ClinVar contains an entry for this variant (Variation ID: 567566). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 526 of the IDUA protein (p.Leu526Pro). This variant is present in population databases (rs781136336, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 22976768, 30442156; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 567566). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2021	Observed in apparent homozygous state through newborn screening in an infant with >50% enzymatic activity (Donati et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33072983, 32432561, 33147872, 27535533, 30442156, 22976768, 26260077, 30093709) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -

Mucopolysaccharidosis, MPS-I-H/S

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jan 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.59

T;.

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;.

Vest4

0.85

MVP

0.99

MPC

0.97

ClinPred

0.26

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.98

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