Variant 4-1002112-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000203.5(IDUA):c.923T>C(p.Leu308Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,571,548 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 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.137

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.923T>C	p.Leu308Pro	missense_variant	7/14	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.923T>C	p.Leu308Pro	missense_variant	7/14	2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000282

AC:

AN:

1419410

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

701992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000610

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000193

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.00000855

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Leu308Pro variant in IDUA has been reported in the homozygous state in 2 Mexican individuals with mucopolysaccharidosis (MPS), segregated with disease in 2 affected relatives from 1 family (PMID: 21393040), and has been identified in 0.005% (1/19128) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752337969). 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: 502243) as a VUS by EGL Genetic Diagnostics and Counsyl. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two affected individuals with this variant were also homozygous for a reported pathogenic variant in another gene known to be associated with another type of MPS (VariationID: 550542). However, these two affected individuals have phenotypes that appear to be consistent with both types of MPS, raising the possibility that this variant is also pathogenic (PMID: 21393040). In summary, the clinical significance of the p.Leu308Pro variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 308 of the IDUA protein (p.Leu308Pro). This variant is present in population databases (rs752337969, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21393040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 502243). 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2017	- -

Hurler syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.63

D;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.86

D;.

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

N;N

REVEL

Uncertain

0.63

Sift

Benign

0.33

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.98

D;.

Vest4

0.82

MutPred

0.61

Gain of disorder (P = 0.0772);.;

MVP

0.92

MPC

0.94

ClinPred

0.24

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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