NM_000203.5(IDUA):c.46_57del (p.Ser16_Ala19del) AND Mucopolysaccharidosis type 1
- Germline classification:
- Pathogenic (6 submissions)
- Last evaluated:
- Dec 6, 2024
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000208599.28
Allele description [Variation Report for NM_000203.5(IDUA):c.46_57del (p.Ser16_Ala19del)]
NM_000203.5(IDUA):c.46_57del (p.Ser16_Ala19del)
- Genes:
- IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]
SLC26A1:solute carrier family 26 member 1 [Gene - OMIM - HGNC] - Variant type:
- Deletion
- Cytogenetic location:
- 4p16.3
- Genomic location:
- Preferred name:
- NM_000203.5(IDUA):c.46_57del (p.Ser16_Ala19del)
- Other names:
- NM_000203.5(IDUA):c.46_57del; p.Ser16_Ala19del
- HGVS:
- NC_000004.12:g.987130_987141del
- NG_008103.1:g.5134_5145del
- NG_033042.1:g.11307_11318del
- NG_158244.2:g.330_341del
- NM_000203.5:c.46_57delMANE SELECT
- NM_134425.4:c.576+3998_576+4009del
- NP_000194.2:p.Ser16_Ala19del
- LRG_1277t1:c.46_57del
- LRG_1277:g.5134_5145del
- LRG_1277p1:p.Ser16_Ala19del
- NC_000004.11:g.980907_980918del
- NC_000004.11:g.980918_980929del
- NM_000203.3:c.46_57del
- NM_000203.3:c.46_57delTCGCTCCTGGCC
- NM_000203.4:c.46_57del
- NM_000203.4:c.46_57del12
- NM_000203.4:c.46_57delTCGCTCCTGGCC
- NM_000203.5:c.46_57del12MANE SELECT
- NR_110313.1:n.134_145del
This HGVS expression did not pass validation- Links:
- dbSNP: rs398123260
- Molecular consequence:
- NM_000203.5:c.46_57del - inframe_deletion - [Sequence Ontology: SO:0001822]
- NM_134425.4:c.576+3998_576+4009del - intron variant - [Sequence Ontology: SO:0001627]
- NR_110313.1:n.134_145del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Condition(s)
- Name:
- Mucopolysaccharidosis type 1
- Synonyms:
- IDUA deficiency; MPS I; Mucopolysaccharidosis Type I
- Identifiers:
- MONDO: MONDO:0001586; MedGen: C0023786
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000695973 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Mar 3, 2025) | germline | clinical testing | |
| SCV000816966 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Feb 2, 2026) | germline | clinical testing | |
| SCV002083076 | Natera, Inc. | criteria provided, single submitter (Natera Variant Classification Schema (03/2026)) | Pathogenic (Jan 16, 2026) | germline | clinical testing | |
| SCV004014671 | Illumina Laboratory Services, Illumina | criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) | Pathogenic (Apr 11, 2023) | unknown | clinical testing | |
| SCV005619879 | ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel | reviewed by expert panel (ClinGen LSD ACMG Specifications IDUA V1.0.0) | Pathogenic (Dec 6, 2024) | germline | curation | |
| SCV007108342 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 17, 2025) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
Citations
PubMed
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.
Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..
- PMID:
- 28492532
- PMCID:
- PMC5632818
Bertola F, Filocamo M, Casati G, Mort M, Rosano C, Tylki-Szymanska A, Tüysüz B, Gabrielli O, Grossi S, Scarpa M, Parenti G, Antuzzi D, Dalmau J, Di Rocco M, Dionisi Vici C, Okur I, Rosell J, Rovelli A, Furlan F, Rigoldi M, Biondi A, Cooper DN, et al.
Hum Mutat. 2011 Jun;32(6):E2189-210. doi: 10.1002/humu.21479. Epub 2011 Mar 10.
- PMID:
- 21394825
Details of each submission
From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695973.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (4) |
Description
Variant summary: IDUA c.46_57del12 (p.Ser16_Ala19del) results in an in-frame deletion that is predicted to remove four amino acids from the encoded protein. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. 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_IDUA_J Formos Med Assoc_2002 ). c.46_57del12 has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11735025, 12189649, 21480867, 15300847). ClinVar contains an entry for this variant (Variation ID: 92643). Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV000816966.9
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (5) |
Description
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 gene product 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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Natera, Inc., SCV002083076.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
The c.46_57delTCGCTCCTGGCC variant in IDUA is an in-frame deletion. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 21394825). This variant results in a change to the protein length while preserving reading frame, which may disrupt normal protein structure or function. Given the available evidence, this variant is classified as Pathogenic.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Illumina Laboratory Services, Illumina, SCV004014671.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, SCV005619879.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | not provided |
Description
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)
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV007108342.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: In-frame insertion/deletion in a non-repetitive region that has low conservation; Variant is present in gnomAD <0.01 for a recessive condition (v4: 73 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel for Mucopolysaccharidosis type 1 (ClinVar). Additional information: This variant is heterozygous; This gene is associated with autosomal recessive disease; Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis type 1 (MONDO:0001586).
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Jul 19, 2026