rs398123260

Positions:

• chr4-987118-GCGCTCCTGGCCT-G
• chr4-987118-GCGCTCCTGGCCT-GCGCTCCTGGCCTCGCTCCTGGCCT

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_Supporting PM4 PP4 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.46_57del variant results in an inframe deletion of 4 amino acids (p.Ser16_Ala19del) within the lysosomal signal sequence of IDUA (PM4). This variant is named "134del12" in older literature. At least twelve patients with with variant and a diagnosis of mucopolysaccharidosis type 1 have been reported in the literature. This includes four patients with documented laboratory values showing deficiency of IDUA activity in fibroblasts or leukocytes (PMID:15300847, 21394825, 23786846) one of whom also had documented clinical features consistent with the diagnosis including corneal clouding, joint stiffness, digital contractures, cardiac valve disease, airway obstruction, and developmental delay (PMID:15300847) (PP4). Four individuals have been reported who are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including two confirmed in trans - c.1750C>T (p.Gln584Ter) (PMID:12189649) and p.Trp402Ter (PMID:11735025); and two phase unknown - c.208C>T (p.Gln70Ter) (PMID:21394825) and c.386-2A>G (PMID:11735025). In addition, at least two homozygotes have been reported PMID:7951228, 21394825) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and c.603C>G (p.Tyr201Ter) (PMID:21394825), c.1189+5G>A (PMID:21394825); c.1960T>C (p.Ter654ArgextTer*62) (PMID:21394825), c.1049A>T (p.Asn350Ile) (PMID:12559846) and c.1598C>G (p.Pro533Arg) (PMID:15300847). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. When expressed in COS-7 cells, the variant (labeled as "134del12") resulted in 124.6% of normal activity. A 77-kDa precursor protein was observed on Western blot, compared with a major mature 63-kDa form and a minor 77-kDa precursor in cells transfected with wild-type cDNA. These results suggested that the variant prevents correct posttranslational processing and transport to the lysosome (PMID:12189649) (PS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006251 (69/1103836 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92643). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PM4, PP4, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220509/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: IDUA NM_000203.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.445

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.46_57del	p.Ser16_Ala19del	inframe_deletion	1/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.46_57del	p.Ser16_Ala19del	inframe_deletion	1/14	2	NM_000203.5	ENSP00000425081	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152036 Hom.: 0 Cov.: 36

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: 64 AN: 1293482 Hom.: 0 AF XY: 0.0000596 AC XY: 38 AN XY: 637434

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: 9 AN: 152036 Hom.: 0 Cov.: 36 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

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

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 24, 2020	- -
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, 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

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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

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123260; hg19: chr4-980906;