rs398123260

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_000203.5(IDUA):c.46_57del(p.Ser16_Ala19del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,445,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 36)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

IDUA
NM_000203.5 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.445

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000203.5.

PP5

Variant 4-987118-GCGCTCCTGGCCT-G is Pathogenic according to our data. Variant chr4-987118-GCGCTCCTGGCCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 92643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987118-GCGCTCCTGGCCT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5 linkuse as main transcript	c.46_57del	p.Ser16_Ala19del	inframe_deletion	1/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2 linkuse as main transcript	c.46_57del	p.Ser16_Ala19del	inframe_deletion	1/14	2	NM_000203.5	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152036

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000495

AC:

AN:

1293482

Hom.:

AF XY:

0.0000596

AC XY:

AN XY:

637434

show subpopulations

Gnomad4 AFR exome

AF:

0.0000384

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000362

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000589

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74276

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:

0.000118

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2016	Variant summary: The IDUA c.46_57del12 (Ser16_Ala19del) variant result in an in frame deletion of 4 amino acids that are not located in a known functional domain of Alpha-L-iduronidase. One in silico tool predicts a benign outcome for this variant. Functional studies in cultured skin fibroblasts from patients compound heterozygous for this variant have indicated that this variant results in IDUA activity that is lower than heterozygous carriers. It has been suggested that although the precursor Ser16_Ala19del IDUA is enzymatically active, this may prevent correct post-translational processing and transport to the lysosome (Lee-Chen_J Formos Med Assoc_2002 ). This variant was absent in 6918 control chromosomes, but has been identified in many compound heterozygous MPS1 patients reported in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This variant, c.46_57del, results in the deletion of 4 amino acid(s) of the IDUA protein (p.Ser16_Ala19del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs398123260, gnomAD 0.01%). This variant has been observed in individual(s) with mucopolysacccharidosis (MPS) type I (PMID: 7951228, 12189649, 15300847, 21394825). 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: 92643). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects IDUA function (PMID: 12189649). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 11, 2023	The IDUA c.46_57del (p.Ser16_Ala19del) variant, also referred to as 134del12, is an in-frame deletion of four amino acids at amino acid position 16. The c.46_57del variant has been reported in both a homozygous and compound heterozygous state in multiple individuals with phenotypes consistent with mucopolysaccharidosis type I (PMID: 7951228; PMID: 11735025; PMID: 12189649; PMID: 15300847; PMID: 21480867). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000130 in the European (non-Finnish) population (version 2.1.1). Functional studies conducted in patient cells suggest that this variant results in decreased enzyme activity and may prevent posttranslational processing and transport into the lysosome (PMID: 12189649; PMID: 23786846). Based on the available evidence, the c.46_57del (p.Ser16_Ala19del) variant is classified as pathogenic for mucopolysaccharidosis type I. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2019	In-frame deletion/insertion of 4 amino acids in a non-repeat region predicted to critically alter the protein.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30548430, 21394825, 11735025, 15300847, 21480867, 23786846, 28604952, 12189649, 7951228, 25098213, 21734815) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2016	- -

Mucopolysaccharidosis, MPS-I-S

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The inframe deletion c.46_57del variant has been reported previously in patient affected with Mucopolysaccharidosis Is (Izumi et. al., 2018) and has also been reported in multiple unrelated individuals affected with MPS I (Bertola et. al., 2011; Yogalingam et. al., 2004; Bunge et. al., 1994). Experimental studies have shown that this variant change results in a IDUA protein that is not cleaved post-translationally, which may prevent its proper localization to the lysosome and interfere with its normal function despite its increased enzymatic activity (Lee-Chen et. al., 2002). The p.Ser16_Ala19del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes and has an allele frequency of 0.006415% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This p.Ser16_Ala19del causes deletion of amino acid Serine at position 16 to Alanine at position 19. This variant is not in the repeat region. For these reasons, this variant has been classified as Pathogenic. -

IDUA-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

The IDUA c.46_57del12 variant is predicted to result in an in-frame deletion (p.Ser16_Ala19del). This variant is also referred to as 134del12 in the literature. This variant has been reported in the homozygous and compound heterozygous states in individuals with biochemically confirmed mucopolysaccharidosis IH, also referred to as Hurler syndrome (Table 1, Bunge et al. 1994. PubMed ID: 7951228; Lee-Chen et al. 2002. PubMed ID: 12189649; Table 4, Gheldof et al. 2018. PubMed ID: 30548430; Table 2, Fang et al. 2021. PubMed ID: 34813777). Experimental studies using patient derived fibroblasts indicate this variant abolishes IDUA activity (Table 1, Oussoren et al. 2013. PubMed ID: 23786846). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-980906-GCGCTCCTGGCCT-G). This variant is interpreted as pathogenic. -

Hurler syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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