rs794727239

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PP3_StrongBP6

The NM_000203.5(IDUA):c.245A>C(p.His82Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,272 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H82Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 4.78

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:

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000203.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

BP6

Variant 4-987895-A-C is Benign according to our data. Variant chr4-987895-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195039.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.245A>C	p.His82Pro	missense_variant	2/14	ENST00000514224.2
SLC26A1	NM_022042.4 linkuse as main transcript	c.*938T>G		3_prime_UTR_variant	3/3	ENST00000398516.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.245A>C	p.His82Pro	missense_variant	2/14	2	NM_000203.5	P1	P35475-1
SLC26A1	ENST00000398516.3 linkuse as main transcript	c.*938T>G		3_prime_UTR_variant	3/3	1	NM_022042.4	P1	Q9H2B4-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00000425

AC:

AN:

235412

Hom.:

AF XY:

0.00000779

AC XY:

AN XY:

128316

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457314

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2018	The IDUA c.245A>C (p.His82Pro) missense variant has been reported in two studies and is found in two individuals in a compound heterozygous state (Clarke and Scott 1993; Venturi et al. 2002). These individuals exhibited an intermediate phenotype characteristic of the Hurler-Scheie syndrome form of mucopolysaccharidosis, type I (MPS I), and also carried a known pathogenic stop-gained variant. The p.His82Pro variant was also reported in a heterozygous state in two additional patients with MPS I in whom a second variant was not identified. The variant was not found in 168 tested control chromosomes. The p.His82Pro variant is reported at a frequency of 0.000017 in the European (non-Finnish) population of the Genome Aggregation Database, though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, p.His82Pro is classified as a variant is of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 82 of the IDUA protein (p.His82Pro). This variant is present in population databases (rs794727239, gnomAD 0.002%). This missense change has been observed in individual(s) with MPS I (PMID: 8401515). ClinVar contains an entry for this variant (Variation ID: 195039). 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. -

Hurler syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 19, 2023

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 19, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

Cadd

Pathogenic

Dann

Benign

0.95

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.81

Sift

Benign

0.054

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.85

MVP

0.99

MPC

0.95

ClinPred

0.96

GERP RS

3.5

Varity_R

0.75

gMVP

0.90

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